RU2682679C2 - Novel pyrazole derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to specific compounds that are pyrazole derivatives of curcumin and have structural formulas executed in the claims. These compounds inhibit the aggregation of tau protein and β-amyloid protein, and also they inhibit β-secretase.

EFFECT: they can be used in treatment of Alzheimer's disease and other diseases mediated by these proteins.

4 cl, 41 tbl, 59 ex

Description

FIELD OF THE INVENTION

The present invention relates to a new compound; a tau protein aggregation inhibitor (hereinafter referred to simply as tau), a β-secretase inhibitor and a β-amyloid protein aggregation inhibitor (hereinafter also referred to as Aβ), to its use; and to a new pyrazole derivative that can be used to prevent or treat diseases such as dementia and Alzheimer's disease, and to a pharmaceutical composition containing it.

Prior art

Senile dementia has become a serious medical problem along with the rapid aging of society in recent years, and therefore it is highly desirable to create effective medicines for the treatment of dementia. Already there are many studies regarding Alzheimer's disease, but the cause of this disease is still not clearly defined. Medicines such as acetylcholinesterase inhibitors, including donepezil (Aricept (registered trademark)), galantamine (Reminyl) and rivastigmine (Exelon / Rivastach) and NMDA receptor antagonists, including memantine hydrochloride (Memary), have been used as therapeutic agents for Alzheimer's disease . These drugs are very useful in symptomatic therapy, but are not drugs for fundamental treatment.

Alzheimer's disease is believed to be caused by Aβ aggregation, tau aggregation, and the like. Therefore, a substance that inhibits the aggregation of these proteins can be used as a fundamental therapeutic drug against Alzheimer's disease.

Yang et al. curcumin has been reported to have inhibitory activity against Aβ aggregation, disaggregation activity against Aβ aggregates, and the like. (non-patent literature 1). The authors of the present invention found that curcumin and its derivatives have inhibitory activity against secretase, which is involved in the formation of Aβ (patent literature 1 and 2). Narlawar et al. curcumin derivatives were synthesized by replacing the 1,3-dicarbonyl fragment with a pyrazole ring, and the compounds obtained were reported to have inhibitory activity against tau aggregation (Non-Patent Literature 2).

Cited Patent Literature

Patent Literature 1: WO 2008/066151,

Patent Literature 2: WO 2009/145219

Non-Patent Literature

Non-Patent Literature 1: Fusheng Yang et al., J. Biol. Chem. 2005, Feb 18; 280 (7) 5892-5901

Non-Patent Literature 2: Rajeshwar Narlawar et al., ChemMedChem 2008, 3, 165-172

SUMMARY OF THE INVENTION

Technical problem

As disclosed in the above literature, a curcumin derivative may be a promising candidate for a fundamental therapeutic drug for the treatment of Alzheimer's disease. Given the existing technical background, the purpose of the present invention is to provide new therapeutic agents for the treatment of Alzheimer's disease.

Solution

The authors managed to obtain a new compound on the basis of technical ideas that differ from those that form the basis of the known compounds, and found that such a compound has excellent pharmacological activity. The authors then undertook intensive research to complete the present invention.

As a result of intensive studies to solve the above problems, the authors synthesized a curcumin derivative, replacing the 1,3-dicarbonyl fragment of curcumin with a pyrazole ring, and replacing at least one of the 4-hydroxy-3-methoxyphenyl groups at both ends with a substituent, and found that such a new compound has effective tau aggregation inhibitory activity. The authors also found that this derivative has high brain penetration ability and also has β-secretase inhibitory activity and Aβ aggregation inhibitory activity.

A curcumin derivative in which the 1,3-dicarbonyl fragment of curcumin is replaced with a pyrazole ring is described in Non-Patent Literature 2, etc. A curcumin derivative in which one of the 4-hydroxy-3-methoxyphenyl groups on both ends of the curcumin is substituted with a substituent is disclosed in Patent Literatures 1 and 2, etc. However, a derivative of the present invention that contains a pyrazole ring, and in which at least one of the 4-hydroxy-3-methoxyphenyl groups at both ends is replaced by a substituent, is a new compound with a chemical structure that is unique to the present invention and is different from structures of compounds disclosed in the known literature.

The activity of inhibiting tau aggregation by curcumin derivatives is disclosed in non-patent literature 2. In the literature, the nitrogen atom at position 1 of the pyrazole ring is replaced by various groups, and the activity of inhibiting tau aggregation by said derivatives varies significantly depending on the groups introduced into the ring. However, no modifications were made at both ends of the benzene rings and, thus, all synthesized derivatives contain 4-hydroxy-3-methoxyphenyl groups, like curcumin. Therefore, it is assumed that the specialist who has read Non-Patent Literature 2 will conclude that the group introduced into the pyrazole ring plays an important role in the activity of inhibiting tau aggregation, and that the 4-hydroxy-3-methoxyphenyl groups on both ends are not related to the activity inhibition of tau aggregation. Therefore, one skilled in the art will not attempt to replace the 4-hydroxy-3-methoxyphenyl groups with a substituent.

Thus, the present invention relates to the following.

[1] A compound represented by the following general formula (I):

[Where

R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a C _1-6 alkyl group optionally containing one or more substituents, a C _1-6 alkoxy group optionally containing one or more substituents, mono or di ( C _1-6 alkyl) amino group optionally containing one or more substituents, C _1-6 alkylthio, optionally containing one or more substituents, C _1-6 alkylsulfonyl group optionally having one or more substituents, C _1-6 acyl group optionally sod containing one or more substituents, a C _1-6 acylamino group, optionally containing one or more substituents, a C _2-6 alkenyl group, optionally containing one or more substituents, a C _2-6 alkenyloxy group, optionally containing one or more substituents, mono or di A (C _2-6 alkenyl) amino group optionally containing one or more substituents, a C _2-6 alkenylthio group optionally containing one or more substituents, or a carbamoyl group optionally containing one or more substituents;

R ² represents a group represented by the following general formula (II):

(where each m and n is an integer 0 or 1,

A represents —O—, —NH—, —S—, —SO— or —SO ₂ -,

Y represents a C _1-6 alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group, and

R ³ represents a nitrogen-containing heterocyclic group, optionally containing one or more substituents, a C _1-6 alkoxy group, optionally containing one or more substituents, a mono- or di (C _1-6 alkyl) amino group, optionally containing one or more substituents, a mono- or a di (C _2-6 alkenyl) amino group optionally containing one or more substituents, or a carbamoyl group optionally containing one or more substituents);

R ¹ and R ² can be connected to form a ring together with a benzene ring; and

Ar represents a homocyclic or heterocyclic group, optionally containing one or more substituents],

or its salt.

[2] The compound of [1] or a salt thereof, wherein m is 1 and A is —O—.

[3] The compound according to [2] or a salt thereof, wherein R ² is a morpholinomethoxy group, morpholinoethoxy group, pyridylmethoxy group, pyridylethoxy group, 2-pyrrolidinoethoxy group, 2-piperidinoethoxy group, 2- (4- (substituted) 2-piperazole 1,1-dioxo-1,4-thiazinan-4-yl) ethoxy.

[4] The compound according to [3] or a salt thereof, wherein R ² is a morpholinoethoxy group.

[5] The compound according to [1] or a salt thereof, wherein R ² is a morpholinomethyl group, (4- (substituted) piperazino) methyl group, (1,1-dioxo-1,4-thiazinan-4-yl) methyl group, piperidinomethyl group, pyrrolidinomethyl group, 2-morpholinoethyl group, 2- (4- (substituted) piperazino) ethyl group, 2- (1,1-dioxo-1,4-thiazinan-4-yl) ethyl group, 2 a piperidinoethyl group, a 2-pyrrolidinoethyl group or a 2-morpholinoethanesulfonyl group.

[6] The compound according to [1] or a salt thereof, wherein R ² is a 4- (substituted) piperazino group or a 4- (substituted) -1,4-diazepano group, except when Ar is a homocyclic group, optional containing substitute.

[7] The compound according to any one of paragraphs. [1] - [6] or its salt, where Ar is a bicyclic group containing a benzene skeleton and optionally containing one or more substituents.

[8] The compounds of [7] or a salt thereof, wherein the bicyclic group containing a benzene skeleton is a 1,3-benzodioxol group, a 1,4-benzodioxan-5-yl group, a 1,4-benzodioxan-6 group -yl, a 1,4-benzodioxin-2-yl group, a quinoline group or an indolyl group.

[9] The compound according to any one of paragraphs. [1] to [5] or a salt thereof, wherein Ar is a phenyl group optionally containing one or more substituents, a pyrrolyl group optionally containing one or more substituents, a pyridyl group optionally containing one or more substituents, a pyrazyl group optionally containing one or more substituents, an imidazolyl group optionally containing one or more substituents, or a furyl group optionally containing one or more substituents.

[10] The compound of [6] or a salt thereof, wherein Ar is a pyrrolyl group optionally containing one or more substituents, a pyridyl group optionally containing one or more substituents, a pyrazyl group optionally containing one or more substituents, an imidazolyl group optionally containing one or more substituents, or furyl a group optionally containing one or more substituents.

[11] The compound according to [1] or a salt thereof, wherein Ar is represented by the following general formula (III):

(Where

R ¹ 'represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a C _1-6 alkyl group optionally containing one or more substituents, a C _1-6 alkoxy group optionally containing one or more substituents, mono or di A (C _1-6 alkyl) amino group optionally containing one or more substituents, a C _1-6 alkylthio group optionally containing one or more substituents, a C _1-6 alkylsulfonyl group optionally containing one or more substituents, a C _1-6 acyl group, optionally with holding one or more substituents, C _1-6 acylamino optionally having one or more substituents, C _2-6 alkenyl group optionally having one or more substituents, C _2-6 alkenyloxy, optionally containing one or more substituents, a mono- or di (C ₂ -6 alkenyl) amino group, optionally containing one or more substituents, C _2-6 alkenylthio group optionally containing one or more substituents, or a carbamoyl group optionally having one or more substituents;

R ² 'represents a group represented by the following general formula (IV):

(where each m 'and n' is an integer 0 or 1,

A ′ represents —O—, —NH—, —S—, —SO— or —SO ₂ -,

Y 'represents a C _1-6 alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group, and

R ³ 'represents a nitrogen-containing heterocyclic group, optionally containing one or more substituents, a C _1-6 alkoxy group, optionally containing one or more substituents, a mono- or di (C _1-6 alkyl) amino group, optionally containing one or more substituents, mono either a di (C _2-6 alkenyl) amino group optionally containing one or more substituents, or a carbamoyl group optionally containing one or more substituents), and

R ¹ 'and R ² ' can form a ring together with a benzene ring).

[12] A tau aggregation inhibitor comprising a compound according to any one of claims. [1] - [11] or its salt, as an active ingredient.

[13] A β-secretase inhibitor comprising a compound according to any one of claims. [1] - [11] or its salt, as an active ingredient.

[14] An Aβ aggregation inhibitor, comprising the compounds of any one of claims. [1] - [11] or its salt, as an active ingredient.

[15] A pharmaceutical composition comprising a compound according to any one of claims. [1] - [11] or its salt, as an active ingredient.

[16] The pharmaceutical composition according to [15], intended for the prevention or treatment of diseases in which tau, β-secretase or Aβ are involved.

[17] The use of the compound of claim 1 or a salt thereof in the manufacture of a prophylactic or therapeutic drug for the treatment of diseases in which tau, β-secretase or Aβ is involved.

[18] The compound according to any one of paragraphs. [1] - [11] or its salt, intended for the prevention or treatment of diseases in which tau, β-secretase or Aβ are involved.

[19] A method for preventing or treating diseases involving tau, β-secretase or Aβ, comprising the step of administering to the patient a compound according to [1].

[20] The pharmaceutical composition according to [15], intended to prevent or treat Alzheimer's disease.

[21] The use of a compound according to [1] or a salt thereof in the manufacture of a prophylactic or therapeutic drug for the treatment of Alzheimer's disease.

[22] The compound according to any one of paragraphs. [1] - [11] or its salt, intended to prevent or treat Alzheimer's disease.

[23] A method for preventing or treating Alzheimer's disease, comprising administering to a patient a compound according to [1].

[24] A medicament for oral or parenteral administration, comprising a compound according to any one of claims. [1] - [11] or its salt and one or more pharmacologically acceptable carriers.

The beneficial effects of the present invention

The compound of the present invention is particularly excellent in terms of tau aggregation inhibition activity, β-secretase inhibition activity, Aβ aggregation inhibition activity and / or the like, and therefore is useful as a therapeutic drug for the treatment of Alzheimer's disease and the like. The compound of the present invention also has high penetrating ability in the brain, and therefore can be a highly effective therapeutic drug.

Preferred Embodiments of the Present Invention

The present invention is described in more detail below.

In the present invention, the term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term “C _1-6 alkyl group” means an unbranched or branched alkyl group containing from 1 to 6 carbon atoms, and examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -butyl, n-pentyl, neopentyl and n-hexyl groups. The term “halo C _1-6 alkyl group” means an unbranched or branched alkyl group containing from 1 to 6 carbon atoms, substituted by one or more halogen atoms, which may be the same or different, and examples of such groups include trifluoromethyl, difluoromethyl, perfluoroethyl, hexafluoroisopropyl, perfluoroisopropyl, chloromethyl, bromomethyl, 1-bromoethyl and 2,3-dibromopropyl groups.

The term “C _1-6 alkoxy group” means a straight or branched alkoxy group containing from 1 to 6 carbon atoms, and examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n pentyloxy, isopentyloxy, neopentyloxy and n-hexyloxy groups. The term “halo C _1-6 alkoxy group” means an unbranched or branched alkoxy group containing from 1 to 6 carbon atoms substituted with one or more halogen atoms, which may be the same or different, and examples of such groups include trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoroisopropoxy , chloromethoxy, bromomethoxy, 1-bromoethoxy and 2,3-dibromopropoxy groups.

The term “C _1-6 acyl group” means a straight or branched acyl group containing from 1 to 6 carbon atoms, and examples of such groups include formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, pivaloyl, pentanoyl, 3-methylbutyryl and hexanoyl groups. The term “halo C _1-6 acyl group” means an unbranched or branched acyl group containing from 1 to 6 carbon atoms, substituted by one or more halogen atoms, which may be the same or different, and examples of such groups include chloroformyl, bromoformyl, dichloracetyl, dibromoacetyl and trifluoroacetyl groups.

The term “C _1-6 alkylsulfonyl group” means an unbranched or branched alkylsulfonyl group containing from 1 to 6 carbon atoms, and examples of such groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, sec-butylsulfonyl, sec-butylsulfonyl, , n-pentylsulfonyl, isopentylsulfonyl and n-hexylsulfonyl groups. The term “halo C _1-6 alkylsulfonyl group” means an unbranched or branched alkylsulfonyl group containing from 1 to 6 carbon atoms substituted with one or more halogen atoms, which may be the same or different, and examples of such groups include trifluoromethylsulfonyl, difluoromethylsulfonyl, perfluoroethylsulfonyl perfluoroisopropylsulfonyl, chloromethylsulfonyl, bromomethylsulfonyl, 1-bromoethylsulfonyl and 2,3-dibromopropylsulfonyl groups.

The term “mono- or di (C _1-6 alkyl) amino group” means an amino group mono- or di-substituted with the above C _1-6 alkyl group, and examples of such groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino , tert-butylamino, dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino and diisopropylamino groups. The term “C _1-6 alkylthio group” means a straight or branched alkylthio group containing from 1 to 6 carbon atoms, and examples of such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n pentylthio, isopentylthio and n-hexylthio groups. The term “C _1-6 acylamino group” means an amino group substituted with the above C _1-6 acyl group, and examples of such groups include acetylamino and propionylamino groups.

The term “C _2-6 alkenyl group” means a straight or branched alkenyl group containing from 2 to 6 carbon atoms, and examples of such groups include vinyl, propenyl and butenyl groups. The term “C _2-6 alkenyloxy group” means a straight or branched alkenyloxy group containing from 2 to 6 carbon atoms, and examples of such groups include propenyloxy, butenyloxy and pentenyloxy groups. The term “mono- or di (C _2-6 alkenyl) amino group” means an alkenylamino group mono- or di-substituted with the above C _2-6 alkenyl group, and examples of such groups include vinylamino, propenylamino, butenylamino and divinylamino groups.

The term “C _2-6 alkenylthio group” means a straight or branched alkenylthio group containing from 2 to 6 carbon atoms, and examples of such groups include vinylthio, 1-propenylthio, isopropenylthio, 1-butenylthio, 2-butenylthio and 2-methylallylthio. The term “nitrogen-containing heterocyclic group” means a saturated or unsaturated heterocyclic group containing one or more nitrogen atoms and optionally containing one or more oxygen and / or sulfur atoms, and examples of such groups include pyridyl, pyrimidyl, pyrazyl, morpholino, 4- (substituted ) piperazino (e.g. 4-methylpiperazino, etc.), 1,1-dioxo-1,4-thiazinan-4-yl, piperidino, pyrrolidino, thiazolyl, azepan-1-yl and 4- (substituted) -1 , 4-diazepano (e.g. 4-methyl-1,4-diazepano) groups.

The present invention relates to a compound represented by the following general formula (I):

and to its salt.

In the above general formula (I), R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a C _1-6 alkyl group optionally containing one or more substituents, a C _1-6 alkoxy group optionally containing one or more substituents, a mono- or di (C _1-6 alkyl) amino group optionally containing one or more substituents, a C _1-6 alkylthio group optionally containing one or more substituents, a C _1-6 alkylsulfonyl group optionally containing one or more substituents, C _1-6 and yl group optionally having one or more substituents, C _1-6 acylamino optionally having one or more substituents, C _2-6 alkenyl group optionally having one or more substituents, C _2-6 alkenyloxy, optionally containing one or more substituents, a mono- or di (C _2-6 alkenyl) amino group optionally containing one or more substituents, a C _2-6 alkenylthio group optionally containing one or more substituents, a carbamoyl group optionally containing one or more substituents her, or the like

The substituents in R ¹ are not particularly limited as long as the effects of the present invention are not violated, and examples of such groups include a halogen atom, a hydroxy group, a nitro group, an amino group, a morpholino group, and a pyridyl group. R ^{1 is} preferably a hydroxy group, a C _1-6 alkyl group optionally containing one or more substituents, a C _1-6 alkoxy group optionally containing one or more substituents, or the like, and more preferably is hydroxy, methoxy, ethoxy , morpholinomethoxy, morpholinoethoxy, pyridylmethoxy or pyridylethoxy group or the like. The position of R ¹ on the benzene ring is not particularly limited as long as the effects of the present invention are not violated, but if the position of the carbon atom bonded to the pyrazole ring through the vinyl group corresponds to position 1, then the position of R ¹ on the benzene ring is preferably a position 2 or 3, more preferably position 2. In the above general formula (I), R ² represents a group represented by the following general formula (II):

In the above general formula (II), each m and n is an integer of 0 or 1. A is —O—, —NH—, —S—, —SO—, —SO ₂ - or the like, and preferably represents —O—, —SO ₂ - or the like. Y represents a C _1-6 alkylene group, a C _2-6 alkenylene group, a C _2-6 alkynylene group or the like, and preferably represents a methylene group, an ethylene group or the like. R ³ represents a nitrogen-containing heterocyclic group, optionally containing one or more substituents, a C _1-6 alkoxy group, optionally containing one or more substituents, a mono- or di (C _1-6 alkyl) amino group, optionally containing one or more substituents, a mono- or a di (C _2-6 alkenyl) amino group optionally containing one or more substituents, or a carbamoyl group optionally containing one or more substituents.

The substituents in R ³ in the above general formula (II) are not particularly limited as long as the effects of the present invention are not violated. In cases where R ³ is a nitrogen-containing heterocyclic group, the substituents are preferably a halogen atom, a hydroxy group, a nitro group, an amino group, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo C _{1 -6} alkoxy group, C _1-6 acyl group, halo C _1-6 acyl group, C _1-6 alkylsulfonyl group, halo C _1-6 alkylsulfonyl group or the like. In cases where R ³ is a C _1-6 alkoxy group, the substituents are preferably a methoxy group, an ethoxy group, a 2-methoxyethoxy group or the like. In cases where R ³ is a mono- or di (C _1-6 alkyl) amino group or a mono or di (alkenyl) amino group, the substituents are preferably a C _1-6 alkoxy group, a halo C _1-6 alkoxy group, C _{1 -6} alkylsulfonyl group, halo C _1-6 alkylsulfonyl group or the like. In cases where R ³ is a carbamoyl group, the substituents are preferably a C _1-6 alkyl group, a C _1-6 alkoxy group or the like.

Preferred specific examples of groups representing R ³ include pyridyl, pyrimidyl, pyrazyl, morpholino, 4- (substituted) piperazino (e.g. 4-methylpiperazino), 4- (substituted) -1,4-diazepano (e.g. 4-methyl- 1,4-diazepano), 1,1-dioxo-1,4-thiazinan-4-yl, piperidino, pyrrolidino, thiazolyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, isopropylamino, N, N-bis (2-methoxyethyl ) amino, N-2-methoxyethyl-N-methylamino, N, N-bis (2-methylsulfonylethyl) amino, N-methyl-N- (2-methylsulfonylethyl) amino and dimethylcarbamoyl groups.

Most preferred specific examples of R ² groups include morpholinoethoxy, morpholinomethoxy, pyridylmethoxy, pyridylethoxy, 2-pyrrolidinoethoxy, 2-piperidinoethoxy, 2- (4- (substituted) piperazino) ethoxy, 2- (1,1-dioxo-1, 4-thiazinan-4-yl) ethoxy, morpholinomethyl, (4- (substituted) piperazino) methyl, (1,1-dioxo-1,4-thiazinan-4-yl) methyl, piperidinomethyl, pyrrolidinomethyl, 2-morpholinoethyl, 2 - (4- (substituted) piperazino) ethyl, 2- (1,1-dioxo-1,4-thiazinan-4-yl) ethyl, 2-piperidinoethyl, 2-pyrrolidinoethyl, 2-morpholinoet ansulfonyl, methoxymethoxy, methoxyethoxy, methoxymethyl, methoxyethyl, dimethylamino, diethylamino, isopropylamino, N, N-bis (2-methoxyethyl) amino, N-2-methoxyethyl-N-methylamino, N, N-bis (2-methylsulfonylethyl) N-methyl-N- (2-methylsulfonylethyl) amino, dimethylaminomethyl, diethylaminomethyl, N, N-bis (2-methoxyethyl) aminomethyl, dimethylaminoethoxy, 4- (substituted) piperazino, 4- (substituted) -1,4-diazepano and dimethylcarbamoylethoxy group. The substituents defined by the term “substituted” and enclosed in parentheses are not particularly limited as long as the effects of the present invention are not violated, but preferably represent a hydrogen atom, a C _1-6 alkyl group or the like, and particularly preferably an atom hydrogen, methyl group, ethyl group, isopropyl group or the like. The position of R ² on the benzene ring is not particularly limited as long as the effects of the present invention are not violated, but if the position of the carbon atom bonded to the pyrazole ring through the vinyl group corresponds to position 1, then the position of R ² on the benzene ring is preferably position 3 or 4, more preferably position 4.

In the above general formula (I), R ¹ and R ² may be combined together to form a ring. In this case, R ¹ and R ² form a fused ring or the like. together with a benzene ring to which R ¹ and R ^{2 are} attached. Examples of fused rings include a 1,3-benzodioxol group optionally containing one or more substituents, a 1,4-benzodioxan-5-yl group optionally containing one or more substituents, a 1,4-benzodioxan-6-yl group optionally containing one or more substituents, a 1,4-benzodioxin-6-yl group optionally containing one or more substituents, a 1,4-benzodioxin-2-yl group optionally containing one or more substituents, a quinoline group optionally containing one or more substituents, from hinolinogruppu optionally containing one or more substituents hinoksalinogruppu optionally containing one or more substituents, and the indolyl group optionally containing one or more substituents.

The substituents in the above fused rings are not particularly limited, and examples of such groups include those given as examples for R ¹ , R ^2, and R ³ .

In the above general formula (I), Ar is a homocyclic or heterocyclic group, optionally containing one or more substituents. The substituents are not particularly limited as long as the effects of the present invention are not violated. Preferred examples of such groups include a halogen atom, a hydroxy group, a nitro group, an amino group, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo a C _1-6 alkoxy group, a C _1-6 acyl group, halo C _1-6 acyl group, C _1-6 alkylsulfonyl group and halo C _1-6 alkylsulfonyl group, and particularly preferred examples of such groups include amino, hydroxy, methyl, ethyl, methoxy and ethoxy groups. Preferred examples of homocyclic or heterocyclic groups include monocyclic groups such as phenyl, pyrrolyl, imidazolyl, furyl, pyridyl and pyrazyl groups, and benzene skeleton bicyclic groups.

Preferred examples of benzene skeleton bicyclic groups include 1,3-benzodioxol, 1,4-benzodioxan-5-yl, 1,4-benzodioxan-6-yl, 1,4-benzodioxin-6-yl, 1,4-benzodioxin- 2-yl, quinolino, isoquinolino, quinoxalino and indolyl groups. Particularly preferred examples of indolyl groups optionally containing one or more substituents include a 1-methylindolyl group.

In cases where Ar is a phenyl group optionally containing one or more substituents, Ar is preferably a substituent represented, for example, by the following general formula (III):

In the above general formula (I), R ¹ ′ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a C _1-6 alkyl group optionally containing one or more substituents, a C _1-6 alkoxy group optionally containing one or more substituents, a mono- or di (C _1-6 alkyl) amino group optionally containing one or more substituents, a C _1-6 alkylthio group optionally containing one or more substituents, a C _1-6 alkylsulfonyl group optionally containing one or more substituents , C _1-6 Cilnius group optionally having one or more substituents, C _1-6 acylamino optionally having one or more substituents, C _2-6 alkenyl group optionally having one or more substituents, C _2-6 alkenyloxy, optionally containing one or more substituents, a mono- or di (C _2-6 alkenyl) amino group optionally containing one or more substituents, a C _2-6 alkenylthio group optionally containing one or more substituents, a carbamoyl group optionally containing one or more substituents lei, or the like

The substituents in R ¹ ′ are not particularly limited as long as the effects of the present invention are not violated, and examples of such groups include a halogen atom, a hydroxy group, a nitro group, an amino group, a morpholino group, and a pyridyl group. R ¹ ′ is preferably a hydroxy group, a C _1-6 alkyl group optionally containing one or more substituents, a C _1-6 alkoxy group optionally containing one or more substituents, or the like, and more preferably hydroxy, methoxy, ethoxy, morpholinomethoxy, morpholinoethoxy, pyridylmethoxy or pyridylethoxy group, or the like. The position of R ¹ ′ on the benzene ring is not specifically limited as long as the effects of the present invention are not violated, but in cases where the position of the carbon atom bonded to the pyrazole ring through the vinyl group is defined as position 1, then the position of R ¹ ′ on the benzene ring is preferably position 2 or 3, more preferably position 2.

In the above general formula (III), R ² ′ is a group represented by the following general formula (IV):

In the above general formula (IV), each m ′ and n ′ is an integer of 0 or 1. A ′ is —O—, —NH—, —S—, —SO—, —SO ₂ -, or the like. p., and preferably represents-O-, -SO ₂ - or the like. Y 'represents a C _1-6 alkylene group, a C _2-6 alkenylene group, a C _2-6 alkynylene group or the like, and preferably represents a methylene group, an ethylene group, or the like. R ³ 'represents a nitrogen-containing heterocyclic group, optionally containing one or more substituents, a C _1-6 alkoxy group, optionally containing one or more substituents, a mono- or di (C _1-6 alkyl) amino group, optionally containing one or more substituents, mono or a di (C _2-6 alkenyl) amino group optionally containing one or more substituents, or a carbamoyl group optionally containing one or more substituents.

The substituents in R ³ ′ in the above general formula (IV) are not particularly limited as long as the effects of the present invention are not violated. In cases where R ³ ′ is a nitrogen-containing heterocyclic group, the substituents are preferably a halogen atom, a hydroxy group, a nitro group, an amino group, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo C _1-6 alkoxy, C _1-6 acyl group, halo C _1-6 acyl group, C _1-6 alkylsulfonyl group, halo C _1-6 alkylsulfonyl group or the like. In cases where R ³ ′ is a C _1-6 alkoxy group, the substituents are preferably a methoxy group, an ethoxy group, a 2-methoxyethoxy group or the like. In cases where R ³ ′ is a mono- or di (C _1-6 alkyl) amino group or a mono or di (alkenyl) amino group, the substituents are preferably a C _1-6 alkoxy group, a halo C _1-6 alkoxy group, C _{A 1-6} alkylsulfonyl group, a halo of a C _1-6 alkylsulfonyl group or the like. In cases where R ³ ′ is a carbamoyl group, the substituents are preferably a C _1-6 alkyl group, a C _1-6 alkoxy group or the like.

Preferred specific examples of the groups represented by R ³ ′ include pyridyl, pyrimidyl, pyrazyl, morpholino, 4- (substituted) piperazino (e.g. 4-methylpiperazino), 1,1-dioxo-1,4-thiazinan-4-yl, piperidino , pyrrolidino, thiazolyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, isopropylamino, N, N-bis (2-methoxyethyl) amino, N-2-methoxyethyl-N-methylamino, N, N-bis (2-methylsulfonylethyl) amino , N-methyl-N- (2-methylsulfonylethyl) amino and dimethylcarbamoyl groups.

Most preferred specific examples of the groups represented by R ² ′ include morpholinoethoxy, morpholinomethoxy, pyridylmethoxy, pyridylethoxy, 2-pyrrolidinoethoxy, 2-piperidinoethoxy, 2- (4- (substituted) piperazino) ethoxy, 2- (1,1-dioxo-1 , 4-thiazinan-4-yl) ethoxy, morpholinomethyl, (4- (substituted) piperazino) methyl, (1,1-dioxo-1,4-thiazinan-4-yl) methyl, piperidinomethyl, pyrrolidinomethyl, 2-morpholinoethyl, 2- (4- (substituted) piperazino) ethyl, 2- (1,1-dioxo-1,4-thiazinan-4-yl) ethyl, 2-piperidinoethyl, 2-pyrrolidinoethyl, 2-morpholinoe ansulfonyl, methoxymethoxy, methoxyethoxy, methoxymethyl, methoxyethyl, dimethylamino, diethylamino, isopropylamino, N, N-bis (2-methoxyethyl) amino, N-2-methoxyethyl-N-methylamino, N, N-bis (2-methylsulfonylethyl) N-methyl-N- (2-methylsulfonylethyl) amino, dimethylaminomethyl, diethylaminomethyl, N, N-bis (2-methoxyethyl) aminomethyl, dimethylaminoethoxy and dimethylcarbamoylethoxy groups. The substituents represented by the term “substituted”, enclosed in parentheses, are not particularly limited as long as the present invention is not infringed, but preferably represent a hydrogen atom, a C _1-6 alkyl group or the like, and particularly preferably represent an atom hydrogen, methyl group, ethyl group, isopropyl group or the like. The position of R ² ′ on the benzene ring is not particularly limited as long as the effects of the present invention are not violated, but in cases where the position of the carbon atom bonded to the pyrazole ring through the vinyl group is defined as position 1, then the position of R ² ′ on the benzene ring is preferably position 3 or 4, more preferably position 4.

In the above general formula (III), R ¹ ′ and R ² ′ may be joined together to form a ring. In this case, R ¹ 'and R ² ' form a condensed ring or the like. together with a benzene ring to which R ¹ ′ and R ² ′ are attached. Examples of fused rings include those set forth above for benzene skeleton bicyclic groups.

The substituents represented by the general formula (III) may be the same or may differ from the phenyl group substituted with R ¹ and R ² in the general formula (I). In cases where they are the same, the compound or its salt is easier to synthesize, and therefore industrially preferred.

In the general formula (I), when R ² is a morpholinomethoxy, morpholinoethoxy or pyridylmethoxy group, Ar is particularly preferably a phenyl group, optionally containing one or more substituents (e.g. a morpholinomethoxyphenyl group, a dimethylcarbamoylmethoxyphenyl group, dimethoxyphenyl group or the like), a pyrrolyl group optionally containing one or more substituents, or a bicyclic group having a benzene skeleton and optionally containing one or b more substituents (for example, a 1,3-benzodioxol group, a 1,4-benzodioxan-6-yl group, an indolyl group, a 1-methylindolyl group or the like). In those cases where R ² is a pyridylmethoxy group, Ar is particularly preferably a pyrrolyl group, optionally containing one or more substituents, or a bicyclic skeleton group (for example, a 1-methylindolyl group or the like). Preferably, R ¹ , R ² and / or Ar are basic groups, so that the compounds or their salts are highly soluble in water and therefore can be easily absorbed in the mouth and the like.

A salt of the compound represented by general formula (I) is also included in the present invention. Such a salt is preferably a pharmacologically acceptable salt, and examples thereof include hydrohalic acid salts such hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic acid salts such as sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate; organic carboxylic acid salts such as acetate, oxalate, maleate, tartrate and fumarate; organic sulfonic acid salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphorsulfonate, amino acid salts such as aspartate and glutamate; amine salts such as a trimethylamine salt, triethylamine salt, procaine salt, pyridine salt, and phenethylbenzylamine salt; an alkali metal salt such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; etc. Given water solubility, oral absorption capacity, potency, and the like, hydrochloride and oxalate are preferred.

A compound represented by general formula (I) can be prepared by known methods disclosed, for example, in Rajeshwar Narlawar et al., ChemMedChem 2008, 3, 165-172, WO 2008/066151, WO 2009/145219, or the like, or using any of a combination of methods known from the literature, or methods known per se, or equivalent methods. More specifically, the compound can be obtained, for example, using the following steps 1 and 2, but the methods for their preparation are not limited to them.

Ar ¹ in the above formula is either a phenyl ring substituted with R ¹ and R ² , or a ring represented as Ar in the compounds represented by general formula (I) of the present invention, and Ar ² is different from Ar. In step 1, the aldehyde represented by the general formula (A) is reacted with a compound represented by the general formula (B) in the presence of a solvent and a catalyst to obtain a diketone represented by the general formula (C).

The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethyl acetate, N, N-dimethylacetamide, N, N-dimethylformamide, l-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetonitrile etc. These solvents can be used alone or in combination of two or more types in a mixture in the specified ratio.

The catalyst used in the reaction is also not particularly limited. Examples thereof include bases such as primary amines and secondary amines, and specific examples of the catalyst include n-butylamine, ethanolamine, piperidine, morpholine, etc.

In step 1, a water scavenger can be added to remove the water formed in the reaction. Examples of a water scavenger include alkyl borates, alkyl phosphates, orthoesters, etc., and specific examples thereof include trimethyl orthoformate and tri-n-butyl borate.

In step 1, the quantitative ratio of the aldehyde represented by the general formula (A) and the compound represented by the general formula (B) is not particularly limited as long as the reaction occurs. However, taking into account the effectiveness of the reaction and the like, the amount of the compound is preferably from 0.5 to 10 moles, more preferably from 0.5 to 2 moles, based on 1 mol of aldehyde.

In step 1, the reaction temperature is not particularly limited until the reaction occurs. However, taking into account the reaction efficiency and the like, the reaction temperature is preferably from 0 to 200 ° C, more preferably from 50 to 100 ° C.

In step 1, the duration of the reaction is not specifically limited until the reaction occurs. However, in view of the production efficiency and the like, the reaction time is preferably from 0.5 to 48 hours, more preferably from 1 to 24 hours.

The aldehyde represented by the general formula (A) and the compound represented by the general formula (B) that are used in step 1 may be commercially available products or may be synthesized by known methods (for example, by the method disclosed in WO 2008/066151 or WO 2009 / 145219) or other methods.

In step 2, the diketone represented by the general formula (C) is allowed to react with hydrazine in the presence of a solvent to obtain a compound represented by the general formula (I).

The hydrazine used in the reaction is not particularly limited, and examples thereof include hydrazine monohydrate, aqueous hydrazine, anhydrous hydrazine, hydrazine acetate, hydrazine monohydrochloride, hydrazine dihydrochloride and their derivatives, etc.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include protic solvents such as acetic acid, methanol, ethanol and water; aprotic solvents such as ethyl acetate, toluene, tetrahydrofuran, methylene chloride, chloroform, etc. These solvents can be used separately or, if desired, in a combination of two or more of their types in a mixture in the specified ratio.

In step 2, the quantitative ratio of the diketone represented by the general formula (C) to hydrazine is not particularly limited as long as the reaction occurs. However, taking into account the effectiveness of the reaction and the like, the amount of hydrazine is preferably from 1 to 50 moles, more preferably from 2 to 10 moles, based on 1 mol of diketone.

In step 2, the reaction temperature is not particularly limited until the reaction occurs. However, in view of the reaction efficiency and the like, the reaction temperature is preferably from 20 to 120 ° C, more preferably from 50 to 80 ° C.

In step 2, the duration of the reaction is not specifically limited until the reaction occurs. However, in view of the production efficiency and the like, the reaction time is preferably from 0.2 to 24 hours, more preferably from 0.5 to 6 hours.

The compound of the present invention can be administered to a subject alone or in combination with one or more other compounds of the present invention, or with one or more compounds other than the compounds of the present invention. The compound of the present invention can be administered in the form of a preparation or in the form of a pharmaceutical composition comprising one or more pharmacologically acceptable carriers. The effective dose of a compound of the present invention as an active ingredient and the frequency of administration may vary depending on the dosage form, age, body weight, symptoms, etc. a patient and the like, but the daily dose is usually from about 0.01 to 100 mg / kg, more preferably from about 1 to 50 mg / kg.

The subject is not particularly limited, and examples thereof include mammals such as human, monkey, hamadryl, baboon, chimpanzee, mouse, rat, guinea pig, hamster, rabbit, cat, dog, sheep, goat, pig and cattle.

Methods for administering a preparation or pharmaceutical composition comprising a compound of the present invention as an active ingredient are not particularly limited, and such a preparation or pharmaceutical composition can be administered orally or parenterally by conventional methods. Examples of parenteral administration include rectal administration, nasal administration, transpulmonary administration, dermal administration and injection administration (e.g., intravenous administration, intraspinal administration, epidural administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, intraarterial administration, intraarticular administration, intracardiac administration, intracystic administration, intradermal administration, intracranial administration, intraocular administration, intrathoracic administration, subarachnoid cial administration, intrauterine administration, intraventricular administration and so on).

The form of the preparation or pharmaceutical composition comprising the compound of the present invention as an active ingredient is not particularly limited, and examples of such forms include oral or parenteral preparations such as tablets, powders, granules, capsules, oral solutions, emulsions, elixirs, lemonades, suspensions, syrups, oromucosal tablets, jelly for oral administration, preparations for inhalation, suppositories, preparations for injection, ointments, eye ointments, eye preparations, nasal preparations, ear preparations, plas thyri, solutions for external use.

The dose of a preparation or pharmaceutical composition of the present invention can be determined appropriately depending on the severity of the symptoms, age, gender and body weight of the patient, route of administration, type of salt, specific disease, etc.

Since the compound of the present invention has tau aggregation inhibitory activity, β-secretase inhibitory activity and / or Aβ aggregation inhibitory activity, the compound of the present invention is effective in the prevention and treatment of diseases in which tau, β-secretase or Aβ, such as Alzheimer's disease (familial Alzheimer's disease and sporadic Alzheimer's disease), senile dementia, Down syndrome, Parkinson's disease, Creutzfeldt-Jacob disease, amyot trophic lateral sclerosis, diabetic neuropathy, Huntington’s chorea, multiple sclerosis, etc. Among these nervous diseases, the compound of the present invention is particularly effective for preventing or treating Alzheimer's disease.

The compound of the present invention can be formulated by commonly used methods into dosage forms such as tablets, powders, granules, capsules, oral solutions, emulsions, elixirs, soft drinks, suspensions, syrups, oromucosal tablets, oral jellies, inhalants, suppositories, preparations for injections, ointments, eye ointments, ophthalmic preparations, nasal preparations, ear preparations, plasters, solutions for external use, etc. To formulate in such dosage forms, excipients, binders, lubricants, colorants, and taste and aroma modifying agents that are commonly used to formulate drugs can be used, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, and regulators can also be used. pH values, preservatives, antioxidants and / or the like. Thus, ingredients that are commonly used as raw materials for pharmaceutical preparations can be mixed with the compound and formulated in the usual manner.

For example, in the manufacture of oral preparations, crystalline or amorphous compounds of the present invention are mixed with excipients, and optionally with additives such as binders, disintegrants, lubricants, colorants, flavor modifiers, etc., and are prepared in the form of powders, fine granules granules, tablets, coated tablets, capsules, etc. in the usual ways. Examples of additives include animal and vegetable fats and oils, such as soybean oil, ghee, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and paraffin wax; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols, such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene cured castor oil and polyoxyethylene-polyoxypropylene block copolymers; water soluble polymers such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, polyacrylate, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyalcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate; purified water; etc.

Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, etc. Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, block polymer polypropylene glycol polyoxyethylene etc. Examples of disintegrants include starches, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcium carboxymethyl cellulose, etc. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silicon dioxide, hydrogenated vegetable oil, etc. Examples of dyes include dyes that are approved as drug additives, etc. Examples of flavor and aroma modifiers include cocoa powder, menthol, flavoring powder, menthol oil, borneol, cinnamon powder, etc.

It is not necessary to indicate that in the manufacture of tablets or granules, if necessary, it is possible to coat tablets or granules with sugar or the like. In the preparation of solutions, such as syrups, emulsions, elixirs, lemonades, suspensions and preparations for injection, the compound of the present invention can be mixed, if necessary, with additional additives, such as pH regulators, solubilizers, emulsifiers, disintegrants, isotonic substances, substances that promote dissolution, stabilizers, etc., and prepared in the form of such solutions by conventional methods.

In the manufacture of topical drugs, the production method is not limited, and the preparation can be carried out by conventional methods. So, for the preparation of medicines for topical application, you can use various types of starting materials, which are usually used for medicines, quasi-medicines, cosmetics or the like. as the main ingredients. Specific examples of the main ingredients that can be used include animal and vegetable oils, mineral oils, esters, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyalcohols, water-soluble polymers, clay minerals, insoluble in water, natural or synthetic polymers such as resins, plastics and rubbers, purified water, etc. In addition, if necessary, pH regulators, antioxidants, chelating agents, antibacterial and antifungal agents, colorants, flavor modifiers and / or the like can be added. The main ingredients of topical medicines are not limited to the above ingredients. Other ingredients are added if necessary, and examples thereof include ingredients having differential stimulatory activity, blood flow enhancing agents, bactericides, anti-inflammatory drugs, cellular activators, vitamins, amino acids, moisturizers, keratolytic agents, etc. The amount of basic ingredients added is determined so that their concentration corresponds to the usual concentration of the main ingredients used in the manufacture of topical medicines.

The compounds of the present invention can be either in the form of food or drinks, or in the form of additives to food products.

The food products or drinks of the invention may contain one or more types of food additives that are commonly used for food or drinks, and examples of food additives include sweeteners, colorants, preservatives, thickeners, stabilizers, antioxidants, coloring agents, bleaches, antifungal agents, resinous bases, bitterness, enzymes, optical brighteners, acidifiers, seasonings, emulsifiers, flavor enhancers, processing aids, perfumes and spice extracts. The foods or drinks of the present invention include healthy foods, functional foods, foods for a particular health condition, foods for babies, baby foods, foods for pregnant women and nursing mothers, foods for the elderly, and foods for the sick.

The form of the food or beverage of the invention is not particularly limited. Specific examples of such products include so-called dietary supplements in the form of tablets, granules, powders, energy drinks, or the like. Other examples of such forms include drinks, such as teas, refreshing drinks, bubbly drinks, nutritious drinks, fruit juices and milk drinks; pasta such as buckwheat noodles, wheat noodles, Chinese noodles and instant pasta; sweets and bakery products such as dragees, candies, chewing sweets, chocolate, snacks, biscuits, jellies, jams, creams, cookies and bread; fish or meat products such as fish sausages, ham and sausages; dairy products such as processed milk and fermented milk; fats, oils and their processed products, such as vegetable oils, oils for frying at high temperatures, margarines, mayonnaises, shortenings, whipped cream and gravy; dressings such as sauces and hot sauces; food in heat-resistant packaging, such as curry, stew, pilaf, cereals and rice soups; and frozen desserts such as ice cream, sorbets and ice cubes.

The amount of food or beverage consumed according to the invention is not particularly limited, and can be determined depending on the shape of the food or drink, age, gender, health status, and the like. a subject that consumes said food or drink, and from other conditions.

The compound of the present invention or its salt can be used for a method of treating a disease in which tau, β-secretase or Aβ is involved. Specific examples of such a method include the following (a) to (c):

(a) a therapeutic method for treating a disease in which tau is involved, said method comprising the step of administering a compound represented by general formula (I) or a salt thereof to a patient in a disease of which tau is involved;

(b) a therapeutic method for treating a disease in which β-secretase is involved, said method comprising the step of administering a compound represented by general formula (I) or a salt thereof to a patient in whose disease β-secretase is involved; and

(c) a therapeutic method for treating a disease in which Aβ is involved, said method comprising the step of administering a compound represented by general formula (I) or a salt thereof to a patient in whose disease Aβ is involved.

Diseases in which tau, β-secretase or Aβ are involved preferably include diseases whose mechanism of occurrence involves the participation of tau, β-secretase or Aβ. Specific examples of such diseases include Alzheimer's disease (familial Alzheimer's disease and sporadic Alzheimer's disease), senile dementia, Down syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic nephropathy, Huntington’s chorea, etc. Among them, Alzheimer's disease is preferred.

The route of administration, the dosage form and dose of the compound of the present invention, and the subject who needs to administer the specified compound can be the same as those disclosed above to obtain a preparation comprising the compound of the present invention.

The compound of the present invention can also be used in a method for inhibiting tau aggregation, in a method for inhibiting β-secretase, and in a method for inhibiting Aβ aggregation. Specific examples of such a method include the following (d) to (i):

d) a method for inhibiting tau aggregation, said method comprising the step of administering a compound represented by general formula (I) or a salt thereof to a mammal, including humans, thereby inhibiting tau aggregation in a mammal, including humans;

(e) a method of inhibiting tau aggregation, said method comprising the step of contacting a compound represented by general formula (I) or a salt thereof with tau;

(f) a method for inhibiting β-secretase, said method comprising the step of administering a compound represented by general formula (I) or a salt thereof to a mammal, including humans, thereby inhibiting β-secretase in a living human body;

g) a method for inhibiting β-secretase, said method comprising the step of contacting a compound represented by general formula (I) or a salt thereof with β-secretase;

(h) a method for inhibiting Aβ aggregation, said method comprising the step of administering a compound represented by general formula (I) or a salt thereof to a mammal, including humans, thereby inhibiting Aβ aggregation in a mammal, including humans; and

(i) a method for inhibiting Aβ aggregation, said method comprising the step of contacting a compound represented by general formula (I) or a salt thereof with Aβ;

The salt in the above methods may be a pharmacologically acceptable salt.

The present invention also includes, as an embodiment, the use of a compound of the present invention or a salt thereof in the manufacture of prophylactic or therapeutic drugs for the treatment of diseases in which tau, β-secretase or Aβ is involved. Diseases in which tau, β-secretase or Aβ are involved may be the diseases disclosed above, and preferably Alzheimer's disease.

The present invention also includes, as another embodiment, a compound of the present invention or a salt thereof, intended to prevent or treat diseases involving tau, β-secretase or Aβ. Diseases in which tau, β-secretase or Aβ are involved may be the diseases disclosed above, and preferably Alzheimer's disease.

Examples

Further, the present invention will be disclosed in more detail with reference to examples, etc., but the present invention is not limited to them. Specialists in this field can make various modifications of the invention, without going beyond the scope of the technical idea of the present invention.

In the examples, the compound of the general formula (I) is defined as a mixture of two tautomers represented further by the general formulas (I) and (I '), depending on the measurement conditions of ¹ H-NMR. These two tautomers are isomers of one substance. Therefore, the synthetic compounds in the examples can be referred to either on the basis of the general formula (I) or the general formula (I ').

The compound represented by the general formula (C) above is an important intermediate of the present invention. A compound of general formula (C) may exist in tautomeric forms, including the ketoform and enol form, and said tautomeric forms are the same substance. Therefore, such an intermediate can be named based on any of the general formula (C), general formula (C '), and general formula (C').

The following abbreviations are used in the description.

Table 1 Abbreviations Reagent, solvent, etc. AcOEt Ethyl acetate AcOH Acetic acid CHCl ₃ Chloroform IBCF Isobutyl Chloroformate K ₂ CO ₃ Potassium carbonate Lah Lithium aluminum hydride MgSO ₄ Magnesium sulfate Na ₂ SO ₄ Sodium sulfate

NaHCO ₃ Bicarbonate of soda NaOH Sodium hydroxide PTLC Preparative thin layer chromatography THF Tetrahydrofuran

Example 1: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] morpholine

Example 1-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

To 2.5 g of (E) -6- (1H-indol-6-yl) hex-5-ene-2,4-dione, 44 ml of AcOEt and 1.07 g of boron oxide were added, and the resulting mixture was stirred at 70 ° C for 40 minutes. 2.27 g of 4- (2-morpholinoethoxy) benzaldehyde and 7.07 ml of tributyl borate were successively added to the mixture, and the resulting mixture was stirred at the same temperature for 40 minutes. Then, 0.11 ml of piperidine was added, and the resulting mixture was stirred at 70 ° C for 1.5 hours and allowed to cool again to room temperature. To the resulting reaction mixture was added 22 ml of a 20% aqueous solution of K ₂ CO ₃ and 20 ml of THF, and the resulting mixture was stirred at room temperature for 10 minutes. The organic layer was isolated, washed with brine, dried over MgSO ₄ and concentrated. The resulting residue was purified using silica gel column chromatography (CHCl ₃ / acetone or CHCl ₃ / methanol system) to obtain 1.62 g of the title compound (33% yield).

Example 1-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] morpholine

To 1.5 g of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione, 13 , 5 ml of AcOH and 1.31 ml of hydrazine monohydrate, and the resulting mixture was stirred at 60 ° C for 3 hours. The resulting reaction mixture was again allowed to cool to room temperature, and 18.7 g of K ₂ CO ₃ , 95 ml of cold water, 30 ml of AcOEt and 20 ml of THF were poured into the stirred mixture. The organic layer was isolated, washed with brine, dried over MgSO ₄ and concentrated. The resulting residue was purified using silica gel column chromatography (CHCl ₃ / acetone or CHCl ₃ / methanol system) to give 0.62 g of the title compound (42% yield).

Example 2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1,3-benzodioxol-5-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] -3-methoxyphenoxy] ethyl] morpholine

Example 2-1: Preparation of (1E, 6E) -1- (1,3-benzodioxol-5-yl) -7- [2-methoxy-4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 2-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1,3-benzodioxol-5-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] -3-methoxyphenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 3: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1,3-benzodioxol-5-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] morpholine

Example 3-1: Preparation of (1E, 6E) -1- (1,3-benzodioxol-5-yl) -7- [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5- dion

The title compound was obtained in the same manner as in Example 1-1.

Example 3-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1,3-benzodioxol-5-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 4: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] phenyl] vinyl] -1H-pyrazole -5-yl] vinyl] -1H-indole

Example 4-1: Preparation of 2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] benzoic acid methyl ester

10.0 g of 1-methylpiperazine and 20.2 g of triethylamine are added to 100 ml of ethanol. To the ice-cooled mixture was added dropwise 25 ml of a solution of 24.6 g of 4- (bromomethyl) -2-methoxybenzoic acid methyl ester in ethanol. The resulting mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated. 75 ml of water and 250 ml of methylene chloride are added to the residue, and the organic layer is isolated. The resulting organic layer was dried and concentrated. The resulting residue was purified using an amino silica gel column chromatography (heptane / AcOEt system) to obtain 22.4 g of the title compound (85% yield).

Example 4-2: Preparation of [2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] phenyl] methanol

To a 200 ml suspension of 5.21 g of LAH in ice-cooled THF was added dropwise 50 ml of a solution of 25.5 g of 2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] methyl ester in an argon stream. benzoic acid in THF. The resulting mixture was stirred under ice cooling for 1 hour and then stirred at room temperature for 22 hours. To the ice-cooled reaction mixture, 25 ml of 10% aqueous NaOH was added dropwise. After stirring for 30 minutes, the resulting mixture was filtered through celite. The resulting filtrate was washed with 150 ml of THF and then concentrated. To the residue were added 50 ml of saturated saline and 300 ml of dichloromethane, and the organic layer was isolated. The organic layer is concentrated. The resulting residue was purified using silica gel column chromatography (CHCl ₃ / methanol system) to obtain 22.4 g of the title compound (98% yield).

Example 4-3: Preparation of 2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] benzaldehyde

To a 220 ml solution of 22.2 g of [2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] phenyl] methanol in CHCl _{3 was} added 61.8 g of manganese dioxide, and the resulting mixture was stirred at 55 ° C. within 13 hours. The resulting reaction mixture was allowed to cool. The insoluble material was filtered off, the mother liquor was concentrated to obtain 21.8 g of the title compound (99% yield).

Example 4-4: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] phenyl] hepta-1 6-diene-3,5-dione

To 200 ml of a solution of 7.56 g of (E) -6- (1H-indol-6-yl) hex-5-ene-2,4-dione in AcOEt, 3.24 g of boron oxide was added and the resulting mixture was stirred at 70 ° C for 1 hour. 15 ml of a solution of 8.68 g of 2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] benzaldehyde in AcOEt and 18.3 ml of triisopropyl borate were successively added to the mixture, and the mixture was stirred at the same temperature for 40 minutes. Then add 10 ml of a solution of 0.35 ml of piperidine in AcOEt. The resulting mixture was stirred at 70 ° C for 3 hours and allowed to cool again to room temperature. To the resulting reaction mixture was added 100 ml of a 10% aqueous solution of K ₂ CO ₃ , and the resulting mixture was stirred for 1 hour. The organic layer was isolated and concentrated. The resulting residue was purified using an amino silica gel chromatography column (heptane / AcOEt system) to give 7.14 g of the title compound (47% yield).

Example 4-5: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-methoxy-4 - [(4-methylpiperazin-1-yl) methyl] phenyl] vinyl] -1H -pyrazol-5-yl] vinyl] -1H-indole

The title compound was prepared in the same manner as 20 and in Example 1-2.

Example 5: Preparation of 3,5-bis [(E) -2- [4- (2-morpholinoethoxy) phenyl] vinyl] -1H-pyrazole

Example 5-1: Preparation of (1E, 6E) -1,7-bis [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

To 2.0 g of pentane-2,4-dione was added 10.0 ml of AcOEt and 0.70 g of boron oxide, and the resulting mixture was stirred at 70 ° C for 1 hour. To the resulting reaction mixture, 30 ml of a solution of 9.4 g of 4- (2-morpholinoethoxy) benzaldehyde in AcOEt and 10.7 ml of tributyl borate were successively added, and the resulting mixture was stirred at the same temperature for 1 hour. 0.4 ml of 1-butylamine was added and the resulting mixture was stirred at 70 ° C for 2.5 hours and allowed to cool again to room temperature. To the resulting reaction mixture was added 50 ml of a 10% aqueous solution of K ₂ CO ₃ and 30 ml of THF, and the resulting mixture was stirred at room temperature for 10 minutes. The organic layer was isolated, washed with brine, dried over MgSO ₄ and concentrated. The resulting residue was treated with 100 ml of diethyl ether to give 2.51 g of the title compound as a powder (24% yield).

Example 5-2: Preparation of 3,5-bis [(E) -2- [4- (2-morpholinoethoxy) phenyl] vinyl] -1H-pyrazole

The title compound was prepared in the same manner as in Example 1-2.

Example 6: Preparation of N, N-dimethyl-2- [4 - [(E) -2- [3 - [(E) -2- [4- (2-morpholinoethoxy) phenyl] vinyl] -1H-pyrazole-5 -yl] vinyl] phenoxy] acetamide

Example 6-1: Preparation of (E) -6- [4- (2-morpholinoethoxy) phenyl] hex-5-en-2,4-dione

To 30.0 g of (E) -3- [4- (2-morpholinoethoxy) phenyl] -2-propenoic acid, 600 ml of THF under an argon stream were added. To the resulting ice-cooled mixture, 12.1 g of triethylamine and 15.5 g of IBCF were successively added dropwise. The resulting mixture was stirred at room temperature for 2 hours to obtain acid anhydride. In a separate container under a stream of argon, 200 ml of THF and 16.3 g of acetylacetone are added to 15.5 g of manganese chloride. To the resulting ice-cooled mixture, 17.5 ml of pyridine was added dropwise in 25 minutes. The resulting mixture was stirred at room temperature for 2 hours. To the resulting ice-cooled reaction mixture was added dropwise over 45 minutes the ice-cooled acid anhydride obtained above. The resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was added to 2 L of a saturated aqueous solution of ammonium chloride and 2 L of CHCl ₃ , and the organic layer was isolated. The resulting organic layer was dried over Na ₂ SO ₄ and concentrated.

The resulting residue was dissolved in 100 ml of THF. While the resulting mixture was stirred under ice-cooling, 40 ml of 28% ammonia water was added dropwise. The resulting mixture was stirred at the same temperature for 1 hour. The resulting reaction mixture was added to 1 L of CHCl ₃ and 1 L of brine, and the organic layer was isolated. The resulting organic layer was dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified using silica gel column chromatography (CHCl ₃ / methanol system) to obtain 26.5 g of the title compound (77% yield).

Example 6-2: Preparation of N, N-dimethyl-2- [4 - [(1E, 6E) -7- [4- (2-morpholinoethoxy) phenyl] -3,5-dioxohepta-1,6-

dienyl] phenoxy] acetamide

The title compound was prepared in the same manner as in Example 4-4.

Example 6-3: Preparation of N, N-dimethyl-2- [4 - [(E) -2- [3 - [(E) -2- [4- (2-morpholinoethoxy) phenyl] vinyl] -1H-pyrazole -5-yl] vinyl] phenoxy] acetamide

To 2.70 g of N, N-dimethyl-2- [4 - [(1E, 6E) -7- [4- (2-morpholinoethoxy) phenyl] -3,5-dioxo-hepta-1,6-dienyl] phenoxy] acetamide, 2.80 g of hydrazine dihydrochloride and 54 ml of methanol are added, and the resulting mixture is stirred at 40 ° C. overnight. The resulting reaction mixture was allowed to cool and poured into 200 ml of a saturated aqueous solution of NaHCO ₃ . 600 ml of AcOEt was added to the mixture, and the organic layer was isolated. The resulting organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified using silica gel column chromatography (CHCl ₃ / methanol system) to obtain 1.76 g of the title compound (66% yield).

Example 7: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (3,4-dimethoxyphenyl) vinyl] -1H-pyrazol-3-yl] vinyl] phenoxy ] ethyl] morpholine

Example 7-1: Preparation of (1E, 6E) -1- (3,4-dimethoxyphenyl) -7- [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was prepared in the same manner as in Example 4-4.

Example 7-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (3,4-dimethoxyphenyl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 6-3.

Example 8: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (3H-benzimidazol-5-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] morpholine

Example 8-1: Preparation of (1E, 6E) -1- (3H-benzimidazol-5-yl) -7- [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was prepared in the same manner as in Example 4-4.

Example 8-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (3H-benzimidazol-5-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 6-3.

Example 9: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1H-pyrrol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 9-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1H-pyrrol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 9-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1H-pyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

K 30 mg (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1H-pyrrol-2-yl) hepta-1,6-diene-3,5-dione 1 ml of THF, 3 μl of AcOH and 4 μl of hydrazine monohydrate are added, and the resulting mixture is stirred at 60 ° C for 4 hours. 500 μl AcOH was added to the mixture, and the resulting mixture was stirred at 80 ° C. for 1 hour. 4 μl of hydrazine monohydrate was added to the mixture, and the resulting mixture was stirred at 80 ° C for 1 hour. The resulting reaction mixture was allowed to cool again to room temperature, and a saturated aqueous solution of NaHCO _{3 was} added. After extraction with AcOEt, the organic layer was isolated. The resulting organic layer was washed with brine, dried over MgSO ₄ and concentrated. The resulting residue was purified using PTLC (CHCl ₃ / methanol or AcOEt) to give 8 mg of the title compound (27% yield).

Example 10: Preparation of 3-benzyloxy-N, N-diethyl-4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] aniline

Example 10-1: Preparation of (E) -6- (1-methylindol-6-yl) hex-5-en-2,4-dione

The title compound was prepared in the same manner as in Example 6-1.

Example 10-2: Preparation of (1E, 6E) -1- [2-benzyloxy-4- (diethylamino) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene-3,5- dion

The title compound was obtained in the same manner as in Example 1-1.

Example 10-3: Preparation of 3-benzyloxy-N, N-diethyl-4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazole -3-yl] vinyl] aniline

The title compound was prepared in the same manner as in Example 9-2.

Example 11: Preparation of N, N-diethyl-4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] -3- (2-morpholinoethoxy) aniline

Example 11-1: Preparation of (1E, 6E) -1- [4- (diethylamino) -2- (2-morpholinoethoxy) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene- 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 11-2: Preparation of N, N-diethyl-4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] -3- (2-morpholinoethoxy) aniline

The title compound was prepared in the same manner as in Example 9-2.

Example 12: Preparation of 2 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl] -5- (2 -pyridylmethoxy) phenol

Example 12-1: Preparation of (1E, 6E) -1- [2-hydroxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 12-2: Preparation of 2 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl] -5- (2-pyridylmethoxy) phenol

The title compound was prepared in the same manner as in Example 9-2.

Example 13: Preparation of 4- [2- [2 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] -5- (2-pyridylmethoxy) phenoxy] ethyl] morpholine

Example 13-1: Preparation of 2- (2-morpholinoethoxy) -4- (2-pyridylmethoxy) benzaldehyde

To 1.0 g of 2-hydroxy-4- (2-pyridylmethoxy) benzaldehyde, 30 ml of acetonitrile, 4.26 g of cesium carbonate and 0.85 g of 4- (2-chloroethyl) morpholinohydrochloride are successively added. The resulting mixture was stirred at 90 ° C for 2 hours. To the resulting reaction mixture were added 50 ml of water and 150 ml of AcOEt, and the organic layer was isolated. The resulting organic layer was dried over Na ₂ SO ₄ and concentrated to give 1.56 g of the title compound in quantitative yield.

Example 13-2: (1E, 6E) -1- (1H-indol-6-yl) -7- [2- (2-morpholinoethoxy) -4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene -3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 13-3: Preparation of 4- [2- [2 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] -5- (2-pyridylmethoxy) phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 9-2.

Example 14: Preparation of 4- [2- [3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] ethyl] morpholine

Example 14-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-morpholinoethoxy) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 14-2: Preparation of 4- [2- [3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazole -3-yl] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 15: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] morpholine

Example 15-1: Preparation of (1E, 6E) -1- (1-methylindol-6-yl) -7- [4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 15-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1-methylindol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 16: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-fluoro-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

Example 16-1: Preparation of (1E, 6E) -1- [2-fluoro-4- (2-pyridylmethoxy) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 16-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-fluoro-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

The title compound was prepared in the same manner as in Example 1-2.

Example 17: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] indole

Example 17-1: Preparation of (1E, 6E) -1- (1-methylindol-6-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 17-2: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] indole

The title compound was prepared in the same manner as in Example 1-2.

Example 18: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [4- (4-methylpiperazin-1-yl) phenyl] vinyl] -1H-pyrazol-5- silt] vinyl] indole

Example 18-1: Preparation of (1E, 6E) -1- (1-methylindol-6-yl) -7- [4- (4-methylpiperazin-1-yl) phenyl] hepta-1,6-dien-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 18-2: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [4- (4-methylpiperazin-1-yl) phenyl] vinyl] -1H-pyrazol- 5-yl] vinyl] indole

The title compound was prepared in the same manner as in Example 1-2.

Example 19: Preparation of 2 - [[3-fluoro-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 19-1: Preparation of (E) -3- [2-fluoro-4- (2-pyridylmethoxy) phenyl] -2-propenoic acid

To 1.8 g of malonic acid, 18 ml of pyridine, 2.0 g of 2-fluoro-4- (2-pyridylmethoxy) benzaldehyde and 0.21 ml of piperidine are added. The resulting mixture was stirred at 75 ° C for 1.5 hours and then stirred at 95 ° C for 1 hour. The resulting reaction mixture was cooled with ice, water was added, and 10% hydrochloric acid was added to adjust the pH to 4. The resulting precipitate was isolated by filtration to obtain 2.0 g of the title compound (85% yield).

Example 19-2: Preparation of (E) -6- [2-fluoro-4- (2-pyridylmethoxy) phenyl] hex-5-en-2,4-dione

The title compound was prepared in the same manner as in Example 6-1.

Example 19-3: Preparation of (1E, 6E) -1- [2-fluoro-4- (2-pyridylmethoxy) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 19-4: Preparation of 2 - [[3-fluoro-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 20: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl] phenoxy ] methyl] pyridine

Example 20-1: Preparation of (E) -6- [4- (2-pyridylmethoxy) phenyl] hex-5-en-2,4-dione

The title compound was prepared in the same manner as in Example 6-1.

Example 20-2: Preparation of (1E, 6E) -1- (1-methylpyrrol-2-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 20-3: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 21: Preparation of 4- [2- [3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] ethyl] morpholine

Example 21-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-morpholinoethoxy) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as 15 and in Example 1-1.

Example 21-2: Preparation of 4- [2- [3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazole -3-yl] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 22: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 22-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 22-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 23: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (1,5-dimethylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] -3-methoxyphenoxy] methyl] pyridine

Example 23-1: Preparation of (1E, 6E) -1- (1,5-dimethylpyrrol-2-yl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 23-2: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (1,5-dimethylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] -3-methoxyphenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 24: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1,3,5-trimethylpyrrol-2-yl) vinyl] -1H-pyrazole -3-yl] vinyl] phenoxy] methyl] pyridine

Example 24-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1,3,5-trimethylpyrrol-2-yl) hepta-1,6- diene 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 24-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1,3,5-trimethylpyrrol-2-yl) vinyl] -1H -pyrazol-3-yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 25: Preparation of 2 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -6-methylpyridine

Example 25-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (6-methyl-2-pyridyl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 25-2: Preparation of 2 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -6-methylpyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 26: Preparation of 3 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -2-methylpyridine

Example 26-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (2-methyl-3-pyridyl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 26-2: Preparation of 3 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -2-methylpyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 27: Preparation of l-methyl-4- [4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl] phenyl] piperazine

Example 27-1: Preparation of (E) -6- (1-methylpyrrol-2-yl) hex-5-en-2,4-dione

The title compound was prepared in the same manner as in Example 6-1.

Example 27-2: Preparation of (1E, 6E) -1- [4- (4-methylpiperazin-1-yl) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 27-3: Preparation of l-methyl-4- [4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3- il] vinyl] phenyl] piperazine

The title compound was prepared in the same manner as in Example 1-2.

Example 28: Preparation of l-methyl-4- [4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl] phenyl] -1,4-diazepane

Example 28-1: Preparation of (1E, 6E) -1- [4- (4-methyl-1,4-diazepan-1-yl) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1, 6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 28-2: Preparation of l-methyl-4- [4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3- yl] vinyl] phenyl] -1,4-diazepane

The title compound was prepared in the same manner as in Example 1-2.

Example 29: Preparation of 3 - [(E) -2- (4-isopropoxy-2-methoxyphenyl) vinyl] -5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazole

Example 29-1: Preparation of (1E, 6E) -1- (4-isopropoxy-2-methoxyphenyl) -7- (1-methylpyrrol-2-yl) hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 29-2: Preparation of 3 - [(E) -2- (4-isopropoxy-2-methoxyphenyl) vinyl] -5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H- pyrazole

The title compound was prepared in the same manner as in Example 1-2.

Example 30: Preparation of l-methyl-4- [2- [4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenyl] ethyl] piperazine

Example 30-1: Preparation of 4- [2- (4-methylpiperazin-1-yl) ethyl] benzaldehyde

To 87 ml of a solution of 8.7 g of l- [2- (4-bromophenyl) ethyl] -4-methylpiperazine in THF, cooled to -70 ° C, 21.1 ml of a solution of n-butyllithium (1.6 mol / l) in hexane, and the resulting mixture was stirred at the same temperature for 30 minutes. While the resulting reaction mixture was stirred at the same temperature, 3.6 ml of N, N-dimethylformamide was added dropwise. The mixture was stirred at the same temperature for 30 minutes. The cooling bath was removed, and the resulting mixture was allowed to warm to -10 ° C, poured into a mixture of 12 ml of 1 N. hydrochloric acid and 100 ml of cold water, and extracted with CHCl ₃ . The resulting extract was dried over MgSO ₄ and concentrated to give 7.04 g of the title compound (98%).

Example 30-2: Preparation of (1E, 6E) -1- [4- [2- (4-methylpiperazin-1-yl) ethyl] phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6 -diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 30-3: Preparation of l-methyl-4- [2- [4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazole -3-yl] vinyl] phenyl] ethyl] piperazine

The title compound was prepared in the same manner as in Example 1-2.

Example 31: Preparation of 2- [2- [3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] ethyl] pyridine

Example 31-1: Preparation of 2-methoxy-4- [2- (2-pyridyl) ethoxy] benzaldehyde

To a stirred, ice-cooled mixture of 5.0 g of 4-hydroxy-2-methoxybenzaldehyde, 4.5 g of 2- (2-pyridyl) ethanol and 10.3 g of triphenylphosphine, 15.8 g of a 40% solution of diethyl azodicarboxylate in toluene are added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, purified using silica gel column chromatography (hexane / acetone system), and further purified using silica gel column chromatography (hexane / AcOEt system) to obtain 5.84 g of the title compound (69% yield).

Example 31-2: Preparation of (1E, 6E) -1- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6 -diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 31-3; Preparation of 2- [2- [3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl] phenoxy] ethyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 32: Preparation of 2 - [[3-methyl-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 32-1: Preparation of 2-methyl-4- (2-pyridylmethoxy) benzoic acid methyl ester

To 0.85 g of 4-hydroxy-2-methylbenzoic acid methyl ester, 12 ml of acetonitrile, 2.12 g of K ₂ CO ₃ and 0.84 g of 2-chloromethyl) pyridine hydrochloride were added, and the resulting mixture was stirred at 90 ° C for 4 hours. The reaction mixture was allowed to cool again to room temperature and neutralized by adding 5% hydrochloric acid. 150 ml of AcOEt was added and the organic layer was isolated. The resulting organic layer was washed with brine, dried over MgSO ₄ and concentrated. The resulting residue was purified using silica gel column chromatography (hexane / AcOEt system) to obtain 1.18 g of the title compound (89% yield).

Example 32-2: Preparation of [2-methyl-4- (2-pyridylmethoxy) phenyl] methanol

To 1.0 g of 2-methyl-4- (2-pyridylmethoxy) benzoic acid methyl ester, 8 ml of toluene under argon atmosphere was added. To the resulting mixture, cooled to −78 ° C., 8.7 ml of a solution of diisobutylaluminum hydride (1.0 mol / L) in toluene are added dropwise. The resulting mixture was stirred at the same temperature for 6 hours and then stirred at -35 ° C for 1 hour. A saturated aqueous Rochelle salt solution was added to the resulting reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. 150 ml of diethyl ether were added to the mixture, and the organic layer was isolated. The resulting organic layer was dried over Na₂SO_fourand concentrated to afford 0.83 g of the title compound (93% yield).

Example 32-3: Preparation of 2-methyl-4- (2-pyridylmethoxy) benzaldehyde

To 0.72 g of [2-methyl-4- (2-pyridylmethoxy) phenyl] methanol was added 30 ml of CHCl ₃ and 7.2 g of manganese dioxide, and the resulting mixture was stirred at room temperature for 2 hours. The insoluble matter was filtered off from the reaction mixture, and the mother liquor was concentrated to obtain 0.70 g of the title compound (99% yield).

Example 32-4: Preparation of (1E, 6E) -1- [2-methyl-4- (2-pyridylmethoxy) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 32-5: Preparation of 2 - [[3-methyl-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] ethyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 33: Preparation of 2- [2- [3 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] pyridine

Example 33-1: Preparation of (1E, 6E) -1- (1-methylpyrrol-2-yl) -7- {3- [2- (2-pyridyl) ethoxy] phenyl] hepta-1,6-diene-3 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 33-2: Preparation of 2- [2- [3 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 34: Preparation of 2 - [[3,5-dimethoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

Example 34-1: Preparation of 2,6-dimethoxy-4- (2-pyridylmethoxy) benzaldehyde

The title compound was obtained in the same manner as in Example 32-1.

Example 34-2: Preparation of (1E, 6E) -1- [2,6-dimethoxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methylpyrrol-2-yl) hepta-1,6-diene- 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 34-3: Preparation of 2 - [[3,5-dimethoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylpyrrol-2-yl) vinyl] -1H-pyrazole -3-yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 35: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylimidazol-2-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 35-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methylimidazol-2-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 35-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (1-methylimidazol-2-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 36: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (3-methylimidazol-4-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 36-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (3-methylimidazol-4-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 36-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (3-methylimidazol-4-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 37: Preparation of 2 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] pyridine

Example 37-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (2-pyridyl) hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 37-2: Preparation of 2 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 38: Preparation of 7 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] quinoline

Example 38-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (7-quinolyl) hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 38-2: Preparation of 7 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] quinoline

The title compound was prepared in the same manner as in Example 1-2.

Example 39: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (2-furyl) vinyl] -1H-pyrazol-3-yl] vinyl] -3-methoxyphenoxy] methyl] pyridine

Example 39-1: Preparation of (1E, 6E) -1- (2-furyl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 39-2: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (2-furyl) vinyl] -1H-pyrazol-3-yl] vinyl] -3- methoxyphenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 40: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (5-methyl-2-furyl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 40-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (5-methyl-2-furyl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 40-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (5-methyl-2-furyl) vinyl] -1H-pyrazole-3 -yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 41: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (4,5-dimethyl-2-furyl) vinyl] -1H-pyrazol-3-yl] vinyl ] -3-methoxyphenoxy] methyl] pyridine

Example 41-1: Preparation of (1E, 6E) -1- (4,5-dimethyl-2-furyl) -7- [2-methoxy-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene- 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 41-2: Preparation of 2 - [[4 - [(E) -2- [5 - [(E) -2- (4,5-dimethyl-2-furyl) vinyl] -1H-pyrazol-3-yl ] vinyl] -3-methoxyphenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 42: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (2-methylpyrazol-3-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] methyl] pyridine

Example 42-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (2-methylpyrazol-3-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 42-2: Preparation of 2 - [[3-methoxy-4 - [(E) -2- [5 - [(E) -2- (2-methylpyrazol-3-yl) vinyl] -1H-pyrazol-3 -yl] vinyl] phenoxy] methyl] pyridine

The title compound was prepared in the same manner as in Example 1-2.

Example 43: Preparation of l-methyl-6 - [(E) -2- [3 - [(B) -2- [4- (4-methyl-1,4-diazepan-1-yl) phenyl] vinyl] - 1H-pyrazol-5-yl] vinyl] indole

Example 43-1: Preparation of (1E, 6E) -1- [4- (4-methyl-1,4-diazepan-1-yl) phenyl] -7- (1-methylindol-6-yl) hepta-1, 6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 43-2: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [4- (4-methyl-1,4-diazepan-1-yl) phenyl] vinyl ] -1H-pyrazol-5-yl] vinyl] indole

The title compound was prepared in the same manner as in Example 1-2.

Example 44: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] vinyl] -1H-pyrazole-5 -yl] vinyl] -1-methylindole

Example 44-1: Preparation of (1E, 6E) -1- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] -7- (1-methylindol-6-yl) hepta-1,6 -diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 44-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] vinyl] -1H-pyrazole -5-yl] vinyl] -1-methylindole

The title compound was prepared in the same manner as in Example 1-2.

Example 45: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2,6-dimethoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

Example 45-1: Preparation of (1E, 6E) -1- [2,6-dimethoxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene- 3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 45-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2,6-dimethoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazole-5- silt] vinyl] -1-methylindole

The title compound was prepared in the same manner as in Example 1-2.

Example 46: Preparation of 6 - [(E) -2- [3 - [(E) -2- [3-fluoro-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

Example 46-1: Preparation of (1E, 6E) -1- [3-fluoro-4- (2-pyridylmethoxy) phenyl] -7- (1-methylindol-6-yl) hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 46-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [3-fluoro-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

The title compound was prepared in the same manner as in Example 1-2.

Example 47: Preparation of 4 - [[4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl] phenyl ] methyl] morpholine

Example 47-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (morpholinomethyl) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 47-2: Preparation of 4 - [[4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenyl] methyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 48: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenyl] ethyl] morpholine

Example 48-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (2-morpholinoethyl) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 48-2: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenyl] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 49: Preparation of 4- [3- [4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenyl] propyl] morpholine

Example 49-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- (3-morpholinopropyl) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 49-2: Preparation of 4- [3- [4 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenyl] propyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 50: Preparation of 6 - [(E) -2- [3 - [(E) -2- [4 - [(4-methylpiperazin-1-yl) methyl] phenyl] vinyl] -1H-pyrazol-5-yl ] vinyl] -IH-indole

Example 50-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [4 - [(4-methylpiperazin-1-yl) methyl] phenyl] hepta-1,6-diene -3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 50-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [4 - [(4-methylpiperazin-1-yl) methyl] phenyl] vinyl] -1H-pyrazol-5 -yl] vinyl] -1H-indole

The title compound was prepared in the same manner as in Example 1-2.

Example 51: Preparation of 6 - [(E) -2- [3 - [(E) -2- [4- [2- (4-methylpiperazin-1-yl) ethyl] phenyl] vinyl] -1H-pyrazole-5 -yl] vinyl] -1H-indole

Example 51-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [4- [2- (4-methylpiperazin-1-yl) ethyl] phenyl] hepta-1,6 -diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 51-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [4- [2- (4-methylpiperazin-1-yl) ethyl] phenyl] vinyl] -1H-pyrazole -5-yl] vinyl] -1H-indole

The title compound was prepared in the same manner as in Example 1-2.

Example 52: Preparation of 4- [2- [2 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] morpholine

Example 52-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [2- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 52-2: Preparation of 4- [2- [2 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 53: Preparation of 4- [2- [3 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl ] phenoxy] ethyl] morpholine

Example 53-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [3- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 53-2: Preparation of 4- [2- [3 - [(E) -2- [5 - [(E) -2- (1H-indol-6-yl) vinyl] -1H-pyrazol-3-yl ] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 54: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] vinyl] -1H-pyrazole-5 -yl] vinyl] -1H-indole

Example 54-1: Preparation of (1E, 6E) -1- (1H-indol-6-yl) -7- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] hepta-1,6 -diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 54-2: Preparation of 6 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- [2- (2-pyridyl) ethoxy] phenyl] vinyl] -1H-pyrazole -5-yl] vinyl] -1H-indole

The title compound was prepared in the same manner as in Example 1-2.

Example 55: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (2,3-dihydro-1,4-benzodioxin-6-yl) vinyl] -1H -pyrazol-3-yl] vinyl] -3-methoxyphenoxy] ethyl] morpholine

Example 55-1: Preparation of (E) -6- (2,3-dihydro-1,4-benzodioxin-6-yl) hex-5-en-2,4-dione

The title compound was prepared in the same manner as in Example 6-1.

Example 55-2: Preparation of (1E, 6E) -1- (2,3-dihydro-1,4-benzodioxin-6-yl) -7- [2-methoxy-4- (2-morpholinoethoxy) phenyl] hepta- 1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 55-3: Preparation of 4- [2- [4 - [(E) -2- [5 - [(E) -2- (2,3-dihydro-1,4-benzodioxin-6-yl) vinyl] -1H-pyrazol-3-yl] vinyl] -3-methoxyphenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 56: Preparation of 4- [2- [3-methoxy-4 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-morpholinoethoxy) phenyl] vinyl] - 1H-pyrazol-5-yl] vinyl] phenoxy] ethyl] morpholine

Example 56-1: Preparation of (1E, 6E) -1,7-bis [2-methoxy-4- (2-morpholinoethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 5-1.

Example 56-2: Preparation of 4- [2- [3-methoxy-4 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-morpholinoethoxy) phenyl] vinyl ] -1H-pyrazol-5-yl] vinyl] phenoxy] ethyl] morpholine

The title compound was prepared in the same manner as in Example 1-2.

Example 57: Preparation of l-methyl-2 - [(E) -2- [3 - [(E) -2- [4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] indole

Example 57-1: Preparation of (1E, 6E) -1- (1-methylindol-2-yl) -7- [4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 57-2: Preparation of l-methyl-2 - [(E) -2- [3 - [(E) -2- [4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] indole

The title compound was prepared in the same manner as in Example 1-2.

Example 58: Preparation of 5 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

Example 58-1: Preparation of (1E, 6E) -1- [2-methoxy-4- (2-pyridylmethoxy) phenyl] -7- (1-methylindol-5-yl) hepta-1,6-diene) -3 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 58-2: Preparation of 5 - [(E) -2- [3 - [(E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazol-5-yl] vinyl] -1-methylindole

The title compound was prepared in the same manner as in Example 1-2.

Example 59: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [2-methyl-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazole-5- silt] vinyl] indole

Example 59-1: Preparation of (1E, 6E) -1- (1-methylindol-6-yl) -7- [2-methyl-4- (2-pyridylmethoxy) phenyl] hepta-1,6-diene-3, 5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 59-2: Preparation of l-methyl-6 - [(E) -2- [3 - [(E) -2- [2-methyl-4- (2-pyridylmethoxy) phenyl] vinyl] -1H-pyrazole- 5-yl] vinyl] indole

The title compound was prepared in the same manner as in Example 1-2.

Structural formulas and analytical data obtained in the above examples are presented in the tables below.

In the tables: Ex .: example; St .: chemical structure; Dat .: analytical data.

table 2 Ex. St. Dat. 1-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.61 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz), 3.72-3.76 (m, 4H) 4.15 (t, 2H, J = 5.7 Hz), 5.81 (s, 1H), 6.51 (d, 1H, J = 16.0 Hz), 6.56-6.58 ( m, 1H), 6.64 (d, 1H, J = 16.0 Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.28-7.30 (m, 1H), 7.40 (dd, 1H, J = 1.3 Hz, 8.2 Hz), 7.50 (d, 2H, J = 8.8 Hz), 7.56 (s, 1H), 7.62 ( d, 1H, J = 16.0 Hz), 7.63 (d, 1H, J = 8.2 Hz), 7.79 (d, 1H, J = 16.0 Hz), 8.30 (s, 1H), 16.07 (br s, 1H)
MS (EI) m / z 444 (M ⁺ ).

1-2

¹ H NMR (δ CDCl ₃ ): 2.55-2.60 (m, 4H), 2.80 (t, 2H, J = 5.7 Hz), 3.72-3.75 (m, 4H) 4.11 (t, 2H, J = 5.7 Hz), 6.52-6.54 (m, 1H), 6.60 (s, 1H), 6.87 (d, 2H, J = 8 , 7 Hz), 6.92 (d, 1H, J = 16.4 Hz), 7.01-7.06 (m, 2H), 7.18-7.20 (m, 1H), 7.19 (d, 1H, J = 16.4 Hz), 7.31 (dd, 1H, J = 1.4 Hz, 8.3 Hz), 7.40 (d, 2H, J = 8.7 Hz), 7.43-7.45 (m, 1H), 7.60 (d, 1H, J = 8.3 Hz), 8.13 (s, 1H), 9.32-11.42 (br, 1H )
MS (EI) m / z 440 (M ⁺ ). 2-1

MS (EI) m / z 479 (M ⁺ ) 2-2

¹ H NMR (δ CDCl ₃ ): 2.61-2.74 (m, 4H), 2.84-2.93 (m, 2H), 3.76-3.83 (m, 4H), 3, 87 (s, 3H), 4.16-4.22 (m, 2H), 5.97 (s, 2H), 6.48-6.52 (m, 2H), 6.58 (s, 1H) 6.79 (d, 1H J = 7.8 Hz), 6.88 (d, 1H, J = 16.5 Hz), 6.91-6.97 (m, 2H), 7.00 (d , 1H, J = 16.5 Hz), 7.03 (d, 1H, J = 1.4 Hz), 7.29 (d, 1H, J = 16.5 Hz), 7.43 (d, 1H , J = 8.2 Hz)
MS (EI) m / z 475 (M ⁺ ).

Table 3 3-1

MS (EI) m / z 449 (M ⁺ ).

3-2

¹ H NMR (δ CDCl ₃ ): 2.56-2.60 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz), 3.74 (m, 4H), 4.14 (t, 2H, J = 5.7 Hz), 5.98 (s, 2H), 6.57 (s, 1H), 6.79 (d, 1H, J = 7.8 Hz), 6.84 -6.94 (m, 5H), 6.97-7.04 (m, 3H), 7.40-7.43 (m, 2H), 9.48-11.04 (br, 1H) MS (EI) m / z 445 (M ⁺ ).

Table 4 4-1

¹ H NMR (δ CDCl ₃ ): 2.29 (s, 3H), 2.47 (br s, 8H), 3.52 (s, 2H), 3.88 (s, 3H), 3.91 (s, 3H), 6.94 (d, 1H, J = 7.9 Hz), 7.00 (s, 1H), 7.74 (d, 1H, J = 7.9 Hz) 4-2

¹ H NMR (δ CDCl ₃ ): 2.28 (s, 3H), 2.47 (br s, 8H), 3.49 (s, 2H), 3.87 (s, 3H), 4.66 (s, 2H), 6.86-6.92 (m, 2H), 7.20 (d, 1H, J = 7.7 Hz) 4-3

¹ H NMR (δ CDCl ₃ ): 2.30 (s, 3H), 2.48 (br s, 8H), 3.53 (s, 2H), 3.94 (s, 3H), 6.97 -7.02 (m, 2H), 7.77 (d, 1H, J = 7.7 Hz), 10.42 (s, 1H)

4-4

¹ H NMR (δ DMSO-d ₆ ): 2.16 (s, 3H), 2.37 (br s, 8H), 3.48 (s, 2H), 3.89 (s, 3H), 6 14 (s, 1H), 6.47-6.51 (m, 1H), 6.84-6.99 (m, 3H), 7.02 (s, 1H), 7.43 (d, 1H) , J = 8.3 Hz), 7.48-7.51 (m, 1H), 7.60 (d, 1H, J = 8.3 Hz), 7.66-7.74 (m, 2H) , 7.79 (d, 1H, J = 15.8 Hz), 7.85 (d, 1H, J = 15.9 Hz), 11.41 (br s, 1H)
MS (ESI) m / z 459 (M ⁺ 2H) ⁺ 915 (2M + H) ⁺ . 4-5

¹ H NMR (δ CDCl ₃ ): 2.31 (s, 3H), 2.50 (br s, 8H), 3.51 (s, 2H), 3.91 (s, 3H), 6.54 -6.56 (m, 1H), 6.67 (s, 1H), 6.91-6.94 (m, 2H), 7.05 (d, 1H, J = 16.6 Hz), 7, 07 (d, 1H, J = 16.6 Hz), 7.18-7.28 (m, 2H), 7.34 (dd, 1H, J = 1.5 Hz, 8.5 Hz), 7, 38 (d, 1H, J = 16.6 Hz), 7.47-7.50 (m, 2H), 7.62 (d, 1H, J = 8.0 Hz), 8.21 (br.s , 1H)

Table 5 5-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.61 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz), 3.72-3.76 (m, 8H) 4.15 (t, 4H, J = 5.7 Hz), 5.77 (s, 1H), 6.49 (d, 2H, J = 16.0 Hz), 6.92 (d, 4H, J = 8.9 Hz), 7.50 (d, 4H, J = 8.9 Hz), 7.61 (d, 2H, J = 16.0 Hz), 16.00 (br.s, 1H)
MS (EI) m / z 534 (M ⁺ )

5-2

¹ H NMR (δ CDCl ₃ ): 2.56-2.61 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz), 3.72-3.76 (m, 8H) 4.13 (t, 4H, J = 5.7 Hz), 6.57 (s, 1H), 6.89 (d, 2H, J = 16.4 Hz), 6.89 (d, 4H, J = 8.8 Hz), 7.02 (d, 2H, J = 16.4 Hz), 7.41 (d, 4H, J = 8.8 Hz)
MS (EI) m / z 530 (M ⁺ ). 6-1

¹ H NMR (δ CDCl ₃ ): 2.16 (s, 3H), 2.56-2.60 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz), 3.72 -3.76 (m, 4H), 4.14 (t, 2H, J = 5.7 Hz), 5.62 (s, 1H), 6.34 (d, 1H, J = 15.7 Hz) 6.89-6.93 (m, 2H), 7.45-7.49 (m, 2H), 7.55 (d, 1H, J = 15.8 Hz)
MS (ESI) m / z 318 (M + H) ⁺ 6-2

¹ H NMR (δ CDCl ₃ ): 2.57-2.61 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz), 2.99 (s, 3H), 3.10 (s, 3H), 3.72-3.77 (m, 4H), 4.15 (t, 2H, J = 5.7 Hz), 4.74 (s, 2H), 5.79 (s, 1H), 6.50 (d, 2H, J = 15.7 Hz), 6.90-6.99 (m, 4H), 7.48-7.54 (m, 4H), 7.61 (d , 1H, J = 15.8 Hz), 7.62 (d, 1H, J = 15.8 Hz)
MS (ESI) m / z 508 (M + 2H) ⁺ 6-3

¹ H NMR (δ DMSO-d ₆ ): 2.45-2.52 (m, 4H), 2.69 (t, 2H, J = 5.8 Hz), 2.85 (s, 3H), 3 00 (s, 3H), 3.56-3.60 (m, 4H), 4.10 (t, 2H, J = 5.7 Hz), 4.83 (s, 2H), 6.67 ( s, 1H), 6.87-7.17 (m, 8H), 7.43-7.52 (m, 4H), 12.89 (s, 1H)

Table 6 7-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.62 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz), 3.72-3.77 (m, 4H) , 3.927 (s, 3H), 3.940 (s, 3H), 4.15 (t, 2H, J = 5.6 Hz), 5.80 (s, 1H), 6.50 (d, 2H, J = 15.8 Hz), 6.86-6.95 (m, 3H), 7.07-7.10 (m, 1H), 7.15 (dd, 1H, J = 1.9, 8.3 Hz ), 7.48-7.53 (m, 2H), 7.61 (d, 1H, J = 15.8 Hz), 7.62 (d, 1H, J = 15.9 Hz)
MS (ESI) m / z 466 (M + H) ⁺ 7-2

¹ H NMR (δ CDCl ₃ ): 2.57-2.61 (m, 4H), 2.81 (t, 2H, J = 5.8 Hz), 3.72-3.77 (m, 4H) 3.876 (s, 3H), 3.884 (s, 3H), 4.11 (t, 2H, J = 5.7 Hz), 6.60 (s, 1H), 6.78-7.08 (m, 9H), 7.35-7.40 (m, 2H) 8-1

MS (ESI) m / z 446 (M + H) ⁺ 8-2

¹ H NMR (δ DMSO-d ₆ ): 2.45-2.53 (m, 4H), 2.69 (t, 2H, J = 5.6 Hz), 3.56-3.61 (m, 4H), 4.08-4.13 (m, 2H), 6.72 (s, 1H), 6.90-7.35 (m, 6H), 7.42-7.85 (m, 5H) , 8.19-8.26 (m, 1H), 12.49 (br s, 1H), 12.92 (br s, 1H)

Table 7 9-1

MS (EI) m / z 402 (M ⁺ ). 9-2

¹ H NMR (δ asetone-d ₆ ): 3.90 (s, 3H), 5.23 (s, 2H), 6.10-6.13 (m, 1H), 6.26-6.28 ( m, 1H), 6.56 (s, 1H), 6.65 (dd, 1H, J = 2.6 Hz, 8.4 Hz), 6.74 (d, 1H, J = 2.6 Hz) 6.77 (d, 1H, J = 16.8 Hz), 6.82-6.84 (m, 1H), 7.03 (d, 1H, J = 16.8 Hz), 7.06 ( d, 1H, J = 16.8 Hz), 7.29-7.33 (m, 1H), 7.35 (d, 1H, J = 16.8 Hz), 7.51 (d, 1H, J = 8.4 Hz), 7.56 (br.s.d, 1H, J = 7.7), 7.82 (dt, 1H, J = 1.8 Hz, 7.7 Hz), 8.57-8 , 60 (m, 1H), 10.33 (br s, 1H)
MS (EI) m / z 398 (M ⁺ ). 10-1

MS (EI) m / z 241 (M ⁺ ). 10-2

MS (EI) m / z 506 (M ⁺ ).

10-3

¹ H NMR (δ CDCl ₃ ): 1.13 (t, 6H, J = 7.2 Hz), 3.33 (q, 4H, J = 7.2 Hz), 3.80 (s, 3H), 5.16 (s, 2H), 6.21 (d, 1H, J = 2.0 Hz), 6.31 (dd, 1H, J = 2.0 Hz, 8.7 Hz), 6.46 ( d, 1H, J = 3.1 Hz), 6.55 (s, 1H), 6.88 (d, 1H, J = 16.4 Hz), 7.05 (d, 1H, J = 3.1 Hz), 7.09 (d, 1H, J = 16.4 Hz), 7.21-7.49 (m, 10H), 7.58 (1H, d, J = 8.2 Hz)
MS (EI) m / z 502 (M ⁺ ).

Table 8 11-1

MS (EI) m / z 529 (M ⁺ ). 11-2

¹ H NMR (δ CDCl ₃ ): 1.19 (t, 6H, J = 7.2 Hz), 2.66-2.70 (m, 4H), 2.93 (t, 2H, J = 5, 9 Hz), 3.38 (q, 4H, J = 7.2 Hz), 3.75-3.81 (m, 7H), 4.20 (t, 2H, J = 5.9 Hz), 6 , 19 (d, 1H, J = 2.5 Hz), 6.32 (dd, 1H, J = 2.5 Hz, 8.7 Hz), 6.46 (d, 1H, J = 3.1 Hz ), 6.55 (s, 1H), 6.88 (d, 1H, J = 16.4 Hz), 7.05 (d, 1H, J = 3.1 Hz), 7.10 (d, 1H , J = 16.4 Hz), 7.24 (d, 1H, J = 16.4 Hz), 7.30 (d, 1H, J = 16.4 Hz), 7.33 (dd, 1H, J = 1.5 Hz, 8.2 Hz), 7.39 (d, 1H, J = 8.7 Hz), 7.43 (br.s, 1H), 7.58 (d, 1H, J = 8 , 2 Hz)
MS (EI) m / z 525 (M ⁺ ).

12-1

MS (EI) m / z 452 (M ⁺ ). 12-2

¹ H NMR (δ acetone-d ₆ ): 3.87 (s, 3H), 5.17 (s, 2H), 6.41 (d, 1H, J = 3.1 Hz), 6.57-6 61 (m, 2H), 6.69 (s, 1H), 7.09 (d, 1H, J = 16.9 Hz), 7.15 (d, 1H, J = 16.4 Hz), 7 23 (d, 1H, J = 3.1 Hz), 7.29-7.33 (m, 2H), 7.34 (d, 1H, J = 16.4 Hz), 7.41 (d, 1H, J = 16.9 Hz), 7.48 (d, 1H, J = 8.2 Hz), 7.52 (br.s., 1H, J = 7.7 Hz), 7.54 (d, 1H, J = 8.7 Hz), 7.56 (br.s, 1H), 7.81 (dt, 1H, J-2.1 Hz, 7.7 Hz), 8.56-8.59 ( m, 1H), 8.13-9.43 (br., 1H), 11.20-12.53 (br., 1H)
MS (EI) m / z 448 (M ⁺ ).

Table 9 13-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.61 (m, 4H), 2.85 (t, 2H, J = 5.6 Hz), 3.71-3.74 (m, 4H) 4.18 (t, 2H, J = 5.6 Hz), 5.26 (s, 2H), 6.57-6.59 (m, 1H), 6.62-6.65 (m, 1H ), 7.24-7.28 (m, 1H), 7.47-7.50 (m, 1H), 7.72-7.76 (m, 1H), 7.81 (d, 1H, J = 8.7 Hz), 8.61-8.63 (m, 1H), 10.31 (s, 1H)

13-2

MS (EI) m / z 551 (M ⁺ ). 13-3

¹ H NMR (δ DMSO-d ₆ ): 2.49-2.56 (m, 4H), 2.77-2.82 (m, 2H), 3.59-3.63 (m, 4H), 4.17 (t, 2H, J = 5.7 Hz), 5.22 (s, 2H), 6.40-6.44 (m, 1H), 6.61-6.69 (m, 2H) 6.75-6.79 (m, 1H), 6.98-7.10 (m, 2H), 7.20-7.31 (m, 3H), 7.34-7.40 (m, 2H), 7.46-7.57 (m, 4H), 7.84-7.88 (m, 1H), 8.58-8.61 (m, 1H), 11.18 (br.s, 1H), 12.87 (br.s, 1H)
MS (EI) m / z 547 (M ⁺ ).

Table 10 Ex. St. Dat. 14-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.60 (m, 4H), 2.82 (t, 2H, J = 5.8 Hz), 3.72-3.76 (m, 4H) 3.83 (s, 3H), 3.88 (s, 3H), 4.15 (t, 2H, J = 5.8 Hz), 5.83 (s, 1H), 6.48-6, 53 (m, 3H), 6.64 (d, 1H, J = 16.0 Hz), 6.66 (d, 1H, J = 16.0 Hz), 7.12 (d, 1H, J = 3 , 2 Hz), 7.38 (dd, 1H, J = 1.3, 8.3 Hz), 7.47-7.49 (m, 2H), 7.60 (d, 1H, J = 8, 3 Hz), 7.81 (d, 1H, J = 16.0 Hz), 7.90 (d, 1H, J = 16.0 Hz)
MS (EI) m / z 488 (M ⁺ ).

14-2

¹ H NMR (δ CDCl ₃ ): 2.59-2.63 (m, 4H), 2.83 (t, 2H, J = 5.7 Hz), 3.75-3.78 (m, 4H) 3.79 (s, 3H), 3.86 (s, 3H), 4.14 (t, 2H, J = 5.7 Hz), 6.45-6.50 (m, 3H), 6, 64 (s, 1H), 6.99 (d, 1H, J = 16.6 Hz), 7.06 (d, 1H, J = 3.1 Hz), 7.09 (d, 1H, J = 16 5 Hz), 7.24 (d, 1H, J = 16.6 Hz), 7.30-7.35 (m, 2H), 7.40-7.42 (m, 1H), 7.45 (d, 1H, J = 9.2 Hz), 7.58 (d, 1H, J = 8.2 Hz)
MS (EI) m / z 484 (M ⁺ ). 15-1

MS (EI) m / z 458 (M ⁺ ). 15-2

¹ H NMR (δ CDCl ₃ ): 2.57-2.61 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz), 3.73-3.76 (m, 4H) 3.80 (s, 3H), 4.14 (t, 2H, J = 5.7 Hz), 6.46-6.47 (m, 1H), 6.61 (s, 1H), 6, 88-6.97 (m, 3H), 7.02-7.08 (m, 3H), 7.23 (d, 1H, J = 16.5 Hz), 7.31 (dd, 1H, J = 1.4, 8.3 Hz), 7.40-7.44 (m, 2H), 7.59 (d, 1H, J = 8.3 Hz), 7.77 (d, 1H, J = 8 , 7 Hz)
MS (EI) m / z 454 (M ⁺ ).

Table 11 16-1

MS (EI) m / z 454 (M ⁺ ).

16-2

¹ H NMR (δ CDCl ₃ ): 3.80 (s, 3H), 5.21 (s, 2H), 6.47 (dd, 1H, J = 0.7 Hz, 3.2 Hz), 6, 65 (s, 1H), 6.73 (dd, 1H, J = 2.5 Hz, 12.3 Hz), 6.79 (dd, 1H, J = 2.5 Hz, 8.7 Hz), 7 02 (d, 1H, J = 16.7 Hz), 7.05 (d, 1H, J = 16.9 Hz), 7.06 (d, 1H, J = 3.0 Hz), 7.16 (d, 1H, J = 16.7 Hz), 7.21-7.26 (m, 2H), 7.32 (dd, 1H, J = 1.35 Hz, 8.3 Hz), 7.40 (s, 1H), 7.45-7.51 (m, 2H), 7.59 (d, 1H, J = 8.3 Hz), 7.70-7.75 (m, 1H), 8, 62 (d, 1H, J = 4.3 Hz)
MS (EI) m / z 450 (M ⁺ ). 17-1

¹ H NMR (δ CDCl ₃ ): 3.84 (s, 3H), 5.25 (s, 2H), 5.82 (s, 1H), 6.49-6.53 (m, 2H), 6 67 (d, 1H, J = 15.7 Hz), 7.00-7.02 (m, 2H), 7.13 (d, 1H, J = 3.0 Hz), 7.23-7, 27 (m, 1H), 7.39 (dd, 1H, J = 1.2, 8.4 Hz), 7.48-7.53 (m, 4H), 7.60-7.64 (m, 2H), 7.71-7.75 (m, 1H), 7.83 (d, 1H, J = 15.7 Hz), 8.60-8.63 (m, 1H), 16.11 (br .c, 1H).
MS (EI) m / z 436 (M ⁺ ). 17-2

¹ H NMR (δ CDCl ₃ ): 3.77 (s, 3H), 5.22 (s, 2H), 6.46 (d, 1H, J = 3.0 Hz), 6.62 (s, 1H ), 6.91-6.97 (m, 3H), 7.04-7.10 (m, 3H), 7.22-7.27 (m, 2H), 7.31 (dd, 1H, J = 1.0, 8.3 Hz), 7.40-7.43 (m, 3H), 7.51-7.53 (m, 1H), 7.58 (d, 1H, J = 8.3 Hz), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 432 (M ⁺ ).

Table 12 18-1

¹ H NMR (δ CDCl ₃ ): 2.35 (s, 3H), 2.56 (t, 4H, J = 4.9 Hz), 3.32 (t, 4H, J = 4.9 Hz), 3.83 (s, 3H), 5.81 (s, 1H), 6.44-6.51 (m, 2H), 6.65 (d, 1H, J = 15.7 Hz), 6.89 (d, 2H, J = 8.6 Hz), 7.12 (d, 1H, J = 2.9 Hz), 7.38 (d, 1H, J = 8.3 Hz), 7.44-7 , 50 (m, 3H), 7.58-7.64 (m, 2H), 7.81 (d, 1H, J = 15.7 Hz), 16.15 (br s, 1H)
MS (EI) m / z 427 (M ⁺ ). 18-2

¹ H NMR (δ CDCl ₃ ): 2.38 (s, 3H), 2.57-2.64 (m, 4H), 3.24-3.31 (m, 4H), 3.80 (s, 3H), 6.45-6.48 (m, 1H), 6.60-6.62 (m, 1H), 6.87-6.92 (m, 3H), 6.99-7.10 ( m, 3H), 7.20-7.27 (m, 1H), 7.32 (d, 1H, J = 8.5 Hz), 7.39-7.43 (m, 3H), 7.57 -7.61 (m, 1H)
MS (EI) m / z 423 (M ⁺ ).

Table 13 19-1

¹ H NMR (δ DMSO-d ₆ ): 5.25 (s, 2H), 6.46 (d, 1H, J = 16.1 Hz), 6.92-6.96 (m, 1H), 7 02-7.07 (m, 1H), 7.35-7.39 (m, 1H), 7.52-7.54 (m, 1H), 7.59 (d, 1H, J = 16, 1 Hz), 7.76-7.80 (m, 1H), 7.83-7.88 (m, 1H), 8.58-8.60 (m, 1H), 12.41 (br.c , 1H)
MS (EI) m / z 273 (M ⁺ ).

19-2

¹ H NMR (δ CDCl ₃ ): 2.16 (s, 3H), 5.23 (s, 2H), 5.63-5.64 (m, 1H), 6.44-6.48 (m, 1H), 6.72-6.76 (m, 1H), 6.79-6.82 (m, 1H), 7.25-7.29 (m, 1H), 7.42-7.47 ( m, 1H), 7.48-7.50 (m, 1H), 7.63 (d, 1H, J = 16.1 Hz), 7.72-7.77 (m, 1H), 8.60 -8.63 (m, 1H)
MS (EI) m / z 313 (M ⁺ ). 19-3

¹ H NMR (δ CDCl ₃ ): 3.74 (s, 3H), 5.23 (s, 2H), 5.72 (s, 1H), 6.19-6.22 (m, 1H), 6 37 (d, 1H, J = 15.4 Hz), 6.59 (d, 1H, J = 16.1 Hz), 6.71-6.77 (m, 2H), 6.77-6, 79 (m, 1H), 6.81 (dd, 1H, J = 2.5 Hz, 8.8 Hz), 7.24-7.28 (m, 1H), 7.45-7.51 (m , 2H), 7.61 (d, 1H, J = 15.4 Hz), 7.67 (d, 1H, J = 16.1 Hz), 7.72-7.76 (m, 1H), 8 , 61-8.63 (m, 1H), 16.10 (br.s, 1H)
MS (EI) m / z 404 (M ⁺ ). 19-4

¹ H NMR (δ CDCl ₃ ): 3.70 (s, 3H), 5.21 (s, 2H), 6.14-6.16 (m, 1H), 6.50 (dd, 1H, J = 1.4 Hz, 3.8 Hz), 6.58 (s, 1H), 6.65 (t, 1H, J = 2.1 Hz), 6.71-6.81 (m, 3H), 6 94-7.02 (m, 2H), 7.14 (d, 1H, J = 16.7 Hz), 7.24-7.27 (m, 1H), 7.47 (t, 1H, J = 8.7 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.71-7.75 (m, 1H), 8.62 (d, 1H, J = 4.9 Hz )
MS (EI) m / z 400 (M ⁺ ).

Table 14 20-1

¹ H NMR (δ CDCl ₃ ): 2.15 (s, 3H), 5.24 (s, 2H), 5.61 (s, 1H), 6.34 (d, 1H, J = 16.0 Hz ), 6.99 (d, 2H, J = 8.7 Hz), 7.23 (dd, 1H, J = 5.0 Hz, 7.6 Hz), 7.47 (d, 2H, J = 8 , 7 Hz), 7.48-7.51 (m, 1H), 7.55 (d, 1H, J = 16.0 Hz), 7.69-7.73 (m, 1H), 8.60 -8.62 (m, TH), 15.43 (br s, 1H) 20-2

¹ H NMR (δ CDCl ₃ ): 3.74 (s, 3H), 5.25 (s, 2H), 5.71 (s, 1H), 6.19-6.21 (m, 1H), 6 37 (d, 1H, J = 15.4 Hz), 6.48 (d, 1H, J = 15.8 Hz), 6.71-6.73 (m, 1H), 6.77-6, 78 (m, 1H), 7.00 (d, 2H, J = 8.8 Hz), 7.23-7.27 (m, 1H), 7.48-7.52 (m, 1H), 7 50 (d, 2H, J = 8.8 Hz), 7.59 (d, 1H, J = 15.8 Hz), 7.60 (d, 1H, J = 15.4 Hz), 7.71 -7.75 (m, 1H), 8.61 (d, 1H, J = 4.2 Hz)
MS (EI) m / z 386 (M ⁺ ). 20-3

¹ H NMR (δ CDCl ₃ ): 3.69 (s, 3H), 5.23 (s, 2H), 6.15 (t, 1H, J = 3.2 Hz), 6.49 (dd, 1H , J = 1.5 Hz, 3.7 Hz), 6.54 (s, 1H), 6.64-6.66 (m, 1H), 6.76 (d, 1H, J = 16.2 Hz ), 6.90 (d, 1H, J = 16.5 Hz), 6.96 (d, 1H, J = 16.2 Hz), 6.98 (d, 2H, J = 8.8 Hz), 7.02 (d, 1H, J = 16.5 Hz), 7.22-7.26 (m, 1H), 7.42 (d, 2H, J = 8.8 Hz), 7.52 (d , 1H, J = 7.9 Hz), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 382 (M ⁺ ).

Table 15 21-1

MS (EI) m / z 438 (M ⁺ ). 21-2

¹ H NMR (δ CDCl ₃ ): 2.57-2.60 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz), 3.69 (s, 3H), 3.73 -3.76 (m, 4H), 3.86 (s, 3H), 4.13 (t, 2H, J = 5.7 Hz), 6.13-6.15 (m, 1H), 6, 47-6.51 (m, 3H), 6.54 (s, 1H), 6.63-6.64 (m, 1H), 6.77 (d, 1H, J = 16.0 Hz), 6 95 (d, 1H, J = 16.5 Hz), 6.96 (d, 1H, J = 16.0 Hz), 7.29 (d, 1H, J = 16.5 Hz), 7.43 (d, 1H, J = 8.3 Hz)
MS (EI) m / z 434 (M ⁺ ). 22-1

MS (EI) m / z 416 (M ⁺ ). 22-2

¹ H NMR (δ CDCl ₃ ): 3.68 (s, 3H), 3.84 (s, 3H), 5.23 (s, 2H), 6.13-6.15 (m, 1H), 6 47 (dd, 1H, J = 1.4, 3.4 Hz), 6.54 (s, 1H), 6.55-6.59 (m, 2H), 6.62-6.63 (m , 1H), 6.77 (d, 1H, J = 16.0 Hz), 6.95 (d, 1H, J = 16.5 Hz), 6.96 (d, 1H, J = 16.0 Hz ), 7.22-7.25 (m, 1H), 7.29 (d, 1H, J = 16.5 Hz), 7.42 (d, 1H, J = 8.7 Hz), 7.51 -7.53 (m, 1H), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 412 (M ⁺ ).

Table 16 23-1

¹ H NMR (δ CDCl ₃ ): 2.28 (s, 3H), 3.59 (s, 3H), 3.86 (s, 3H), 5.25 (s, 2H), 5.69 (s , 1H), 5.99 (d, 1H, J = 3.9 Hz), 6.32 (d, 1H, J = 15.5 Hz), 6.56-6.61 (m, 3H), 6 66 (d, 1H, J = 3.9 Hz), 7.24-7.28 (m, 1H), 7.46 (d, 1H, J = 9.3 Hz), 7.50-7, 53 (m, 1H), 7.60 (d, 1H, J = 15.5 Hz), 7.71-7.76 (m, 1H), 7.85 (d, 1H, J = 16.2 Hz ), 8.60-8.63 (m, 1H)
MS (EI) m / z 430 (M ⁺ ). 23-2

¹ H NMR (δ CDCl ₃ ): 2.25 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 5.23 (s, 2H), 5.90-5 95 (m, 1H), 6.40-6.45 (m, 1H), 6.52-6.61 (m, 3H), 6.71 (d, 1H, J = 16.5 Hz), 6.97 (d, 1H, J = 17.0 Hz), 7.03 (d, 1H, J = 16.5 Hz), 7.21-7.35 (m, 2H), 7.42 (d , 1H, J = 8.5 Hz), 7.50-7.54 (m, 1H), 7.69-7.76 (m, 1H), 8.68-8.64 (m, 1H)
MS (EI) m / z 426 (M ⁺ ). 24-1

¹ H NMR (δ CDCl ₃ ): 2.24 (s, 3H), 2.27 (s, 3H), 3.58 (s, 3H), 3.86 (s, 3H), 5.24 (s , 2H), 5.70 (s, 1H), 5.86 (s, 1H), 6.18 (d, 1H, J = 15.5 Hz), 6.56-6.60 (m, 3H) 7.23-7.27 (m, 1H), 7.46 (d, 1H, J = 9.2 Hz), 7.49-7.53 (m, 1H), 7.69-7.75 (m, 2H), 7.84 (d, 1H, J = 16.1 Hz), 8.60-8.63 (m, 1H)
MS (EI) m / z 444 (M ⁺ ).

24-2

¹ H NMR (δ CDCl ₃ ): 2.22 (s, 3H), 2.23 (s, 3H), 3.54 (s, 3H), 3.86 (s, 3H), 5.24 (s , 2H), 5.80 (s, 1H), 6.52-6.60 (m, 4H), 6.97 (d, 1H, J = 16.7 Hz), 7.01 (d, 1H, J = 16.7 Hz), 7.23-7.27 (m, 1H), 7.30 (d, 1H, J = 16.7 Hz), 7.44 (d, 1H, J = 8.3 Hz), 7.51-7.54 (m, 1H), 7.71-7.75 (m, 1H), 8.61-8.63 (m, 1H)
MS (EI) m / z 440 (M ⁺ ).

Table 17 25-1

¹ H NMR (δ CDCl ₃ ): 2.60 (s, 3H), 3.88 (s, 3H), 5.25 (s, 2H), 5.92 (s, 1H), 6.58-6 61 (m, 2H), 6.66 (d, 1H, J = 16.0 Hz), 7.09-7.12 (m, 1H), 7.17 (d, 1H, J = 15.5 Hz), 7.20-7.23 (m, 1H), 7.24-7.27 (m, 1H), 7.48-7.53 (m, 2H), 7.56-7.61 ( m, 2H), 7.71-7.76 (m, 1H), 7.93 (d, 1H, J = 16.0 Hz), 8.61-8.63 (m, 1H), 15.85 (br.s, 1H)
MS (EI) m / z 428 (M ⁺ ). 25-2

¹ H NMR (δ CDCl ₃ ): 2.59 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.60 (m, 2H), 6 68 (s, 1H), 6.97 (d, 1H, J = 16.6 Hz), 7.02-7.04 (m, 1H), 7.16 (d, 1H, J = 16.2 Hz), 7.23-7.27 (m, 2H), 7.30 (d, 1H, J = 16.6 Hz), 7.44 (d, 1H, J = 8.3 Hz), 7, 51-7.58 (m, 3H), 7.71-7.75 (m, 1H), 8.61-8.63 (m, 1H)
MS (EI) m / z 424 (M ⁺ ).

26-1

MS (EI) m / z 428 (M ⁺ ). 26-2

¹ H NMR (δ CDCl ₃ ): 2.67 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.61 (m, 2H), 6 65 (s, 1H), 6.95 (d, 1H, J = 16.4 Hz), 7.00 (d, 1H, J = 16.4 Hz), 7.15 (dd, 1H, J = 4.7, 7.9 Hz), 7.23-7.28 (m, 2H), 7.31 (d, 1H, J = 16.4 Hz), 7.43 (d, 1H, J = 8 6 Hz), 7.53 (d, 1H, J = 7.9 Hz), 7.74 (dt, 1H, J = 1.9, 7.6 Hz), 7.83 (dd, 1H, J = 1.6, 7.9 Hz), 8.40 (dd, 1H, J = 1.6, 4.7 Hz), 8.61-8.63 (m, 1H)
MS (EI) m / z 424 (M ⁺ ).

Table 18 27-1

¹ H NMR (δ CDCl ₃ ): 2.12 (s, 3H), 3.71 (s, 3H), 5.55 (s, 1H), 6.17-6.19 (m, 1H), 6 20 (d, 1H, J = 15.3 Hz), 6.65-6.66 (m, 1H), 6.74-6.75 (m, 1H), 7.52 (d, 1H, J = 15.3 Hz), 15.63 (br.s, 1H)

27-2

¹ H NMR (δ CDCl ₃ ): 2.85 (s, 3H), 3.06 (t, 4H, J = 5.0 Hz), 3.82 (t, 4H, J = 5.0 Hz), 4.22 (s, 3H), 6.19 (s, 1H), 6.68-6.70 (m, 1H), 6.85 (d, 1H, J = 15.4 Hz), 6.94 (d, 1H, J = 16.0 Hz), 7.19 (dd, 1H, J = 1.3 Hz, 3.9 Hz), 7.24-7.26 (m, 1H), 7.38 (d, 2H, J = 8.9 Hz), 7.95 (d, 2H, J = 8.9 Hz), 8.07 (d, 1H, J = 16.0 Hz), 8.08 (d , 1H, J = 15.4 Hz), 16.68 (br s, 1H) MS (EI) m / z 377 (M ⁺ ). 27-3

¹ H NMR (δ CDCl ₃ ): 2.38 (s, 3H), 2.58-2.64 (m, 4H), 3.28 (t, 4H, J = 4.8 Hz), 3.69 (c, 3H), 6.15 (dd, 1H, J = 2.8 Hz, 3.6 Hz), 6.48 (dd, 1H, J = 1.5 Hz, 3.6 Hz), 6, 52 (s, 1H), 6.63-6.65 (m, 1H), 6.76 (d, 1H, J = 16.2 Hz), 6.86 (d, 1H, J = 16.4 Hz ), 6.90 (d, 2H, J = 8.8 Hz), 6.95 (d, 1H, J = 16.2 Hz), 6.99 (d, 1H, J = 16.4 Hz), 7.39 (d, 2H, J = 8.8 Hz)
MS (EI) m / z 373 (M ⁺ ).

Table 19 28-1

¹ H NMR (δ CDCl ₃ ): 2.02 (quintet, 2H, J = 5.9 Hz), 2.38 (s, 3H), 2.54-2.58 (m, 2H), 2.69 -2.73 (m, 2H), 3.52-3.56 (m, 2H), 3.60-3.64 (m, 2H), 3.73 (s, 3H), 5.68 (s , 1H), 6.18-6.21 (m, 1H), 6.36 (d, 1H, J = 15.5 Hz), 6.40 (d, 1H, J = 15.7 Hz), 6 66-6.70 (m, 3H), 6.75-6.77 (m, 1H), 7.42-7.45 (m, 2H), 7.57 (d, 1H, J = 15, 5 Hz), 7.59 (d, 1H, J = 15.6 Hz)
MS (EI) m / z 391 (M ⁺ ).

28-2

¹ H NMR (δ CDCl ₃ ): 2.00-2.06 (m, 2H), 2.39 (s, 3H), 2.55-2.60 (m, 2H), 2.70-2, 74 (m, 2H), 3.50-3.54 (m, 2H), 3.59-3.62 (m, 2H), 3.69 (s, 3H), 6.14-6.16 ( m, 1H), 6.47-6.53 (m, 2H), 6.63-6.69 (m, 3H), 6.78 (d, 1H, J = 16.1 Hz), 6.79 (d, 1H, J = 16.4 Hz), 6.96 (d, 1H, J = 16.1 Hz), 6.98 (d, 1H, J = 16.4 Hz), 7.34-7 , 38 (m, 2H)
MS (EI) m / z 387 (M ⁺ ). 29-1

¹ H NMR (δ CDCl ₃ ): 1.36 (d, 6H, J = 5.8 Hz), 3.73 (s, 3H), 3.86 (s, 3H), 4.57-4.63 (m, 1H), 5.71 (s, 1H), 6.18-6.20 (m, 1H), 6.36 (d, 1H, J = 15.4 Hz), 6.44 (d, 1H, J = 2.4 Hz), 6.49 (dd, 1H, J = 2.4 Hz, 8.5 Hz), 6.59 (d, 1H, J = 15.9 Hz), 6.68 -6.70 (m, 1H), 6.74-6.76 (m, 1H), 7.45 (d, 1H, J = 8.5 Hz), 7.58 (d, 1H, J = 15 4 Hz), 7.87 (d, 1H, J = 15.9 Hz)
MS (EI) m / z 367 (M ⁺ ). 29-2

¹ H NMR (δ CDCl ₃ ): 1.35 (d, 6H, J = 6.1 Hz), 3.69 (s, 3H), 3.85 (s, 3H), 4.53-4.61 (m, 1H), 6.13-6.15 (m, 1H), 6.45 (d, 1H, J = 2.3 Hz), 6.46-6.49 (m, 2H), 6, 54 (s, 1H), 6.62-6.64 (m, 1H), 6.77 (d, 1H, J = 16.2 Hz), 6.95 (d, 1H, J = 16.7 Hz ), 7.01 (d, 1H, J = 16.2 Hz), 7.30 (d, 1H, J = 16.7 Hz), 7.41 (d, 1H, J = 8.5 Hz)
MS (EI) m / z 363 (M ⁺ ).

Table 20 30-1

¹ H NMR (δ CDCl ₃ ): 2.30 (s, 3H), 2.40-2.66 (m, 10H), 2.86-2.90 (m, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.80 (d, 2H, J = 8.0 Hz), 9.98 (s, 1H) 30-2

MS (EI) m / z 405 (M ⁺ ). 30-3

¹ H NMR (δ CDCl ₃ ): 2.30 (s, 3H), 2.43-2.66 (m, 10H), 2.79-2.83 (m, 2H), 3.70 (s, 3H), 6.14-6.16 (m, 1H), 6.49 (dd, 1H, J = 1.4 Hz, 3.7 Hz), 6.55 (s, 1H), 6.64- 6.65 (m, 1H), 6.75 (d, 1H, J = 16.3 Hz), 6.95 (d, 1H, J = 16.5 Hz), 6.98 (d, 1H, J = 16.3 Hz), 7.05 (d, 1H, J = 16.5 Hz), 7.20 (d, 2H, J = 8.1 Hz), 7.40 (d, 2H, J = 8 , 1 Hz)
MS (EI) m / z 401 (M ⁺ ).

Table 21 31-1

MS (EI) m / z 257 (M ⁺ ).

31-2

¹ H NMR (δ CDCl ₃ ): 3.28 (t, 2H, J = 6.6 Hz), 3.73 (s, 3H), 3.86 (s, 3H), 4.42 (t, 2H , J = 6.6 Hz), 5.71 (s, 1H), 6.17-6.21 (m, 1H), 6.36 (d, 1H, J = 15.4 Hz), 6.45 (d, 1H, J = 2.0 Hz), 6.53 (dd, 1H, J = 2.0 Hz, 8.6 Hz), 6.59 (d, 1H, J = 16.0 Hz), 6.90 (d, 1H, J = 3.68 Hz), 6.75 (s, 1H), 7.13-7.18 (m, 1H), 7.24-7.28 (m, 1H) 7.45 (d, 1H, J = 8.6 Hz), 7.58 (d, 1H, J = 15.4 Hz), 7.60-7.66 (m, 1H), 7.87 ( d, 1H, J = 16.0 Hz), 8.57 (d, 1H, J = 4.7 Hz), 16.18 (br s, 1H)
MS (EI) m / z 430 (M ⁺ ). 31-3

¹ H NMR (δ CDCl ₃ ): 3.28 (t, 2H, J = 6.7 Hz), 3.70 (s, 3H), 3.84 (s, 3H), 4.40 (t, 2H , J = 6.7 Hz), 6.15 (t, 1H, J = 3.3 Hz), 6.45 (d, 1H, J = 2.2 Hz), 6.48-6.52 (m , 2H), 6.55 (s, 1H), 6.63-6.65 (m, 1H), 6.77 (d, 1H, J = 16.5 Hz), 6.94 (d, 1H, J = 16.9 Hz), 6.99 (d, 1H, J = 16.5 Hz), 7.17 (dd, 1H, J = 5.1 Hz, 7.45 Hz), 7.25-7 32 (m, 2H), 7.41 (d, 1H, J = 8.6 Hz), 7.62-7.66 (m, 1H), 8.56-8.58 (m, 1H)
MS (EI) m / z 426 (M ⁺ ).

Table 22 32-1

¹ H NMR (δ CDCl ₃ ): 2.59 (s, 3H), 3.85 (s, 3H), 5.24 (s, 2H), 6.82 (dd, 1H, J = 2.5 Hz , 8.8 Hz), 6.85 (d, 1H, J = 2.5 Hz), 7.22-7.26 (m, 1H), 7.48-7.51 (m, 1H), 7 70-7.74 (m, 1H), 7.93 (d, 1H, J = 8.7 Hz), 8.60-8.62 (m, 1H)
MS (EI) m / z 257 (M ⁺ ).

32-2

¹ H NMR (δ CDCl ₃ ): 2.36 (s, 3H), 4.64 (s, 2H), 5.19 (s, 2H), 6.78 (dd, 1H, J = 2.7 Hz , 8.4 Hz), 6.85 (d, 1H, J = 2.6 Hz), 7.21-7.25 (m, 2H), 7.50-7.53 (m, 1H), 7 69-7.73 (m, 1H); 8.58-8.61 (m, 1H)
MS (EI) m / z 229 (M ⁺ ). 32-3

¹ H NMR (δ CDCl ₃ ): 2.65 (s, 3H), 5.27 (s, 2H), 6.86 (d, 1H, J = 2.4 Hz), 6.93 (dd, 1H , J = 2.6 Hz, 8.5 Hz), 7.24-7.27 (m, 1H), 7.48-7.50 (m, 1H), 7.71-7.77 (m, 2H), 8.61-8.63 (m, 1H), 10.12 (s, 1H)
MS (EI) m / z 227 (M ⁺ ). 32-4

¹ H NMR (δ CDCl ₃ ): 2.44 (s, 3H), 3.74 (s, 3H), 5.23 (s, 2H), 5.70 (s, 1H), 6.19-6 21 (m, 1H), 6.37 (d, 1H, J = 15.5 Hz), 6.43 (d, 1H, J = 15.5 Hz), 6.71-6.73 (m, 1H), 6.77-6.78 (m, 1H), 6.83-6.86 (m, 2H), 7.22-7.27 (m, 1H), 7.49-7.52 ( m, 1H), 7.55-7.58 (m, 1H), 7.60 (d, 1H, J = 15.5 Hz), 7.70-7.74 (m, 1H), 7.86 (d, 1H, J = 15.6 Hz), 8.60-8.62 (m, 1H)
MS (EI) m / z 400 (M +).

Table 23 32-5

¹ H NMR (δ CDCl ₃ ): 2.40 (s, 3H), 3.70 (s, 3H), 5.22 (s, 2H), 6.15-6.16 (m, 1H), 6 49 (dd, 1H, J = 1.6 Hz, 3.8 Hz), 6.55 (s, 1H), 6.64-6.66 (m, 1H), 6.77 (d, 1H, J = 16.3 Hz), 6.80-6.85 (m, 3H), 6.96 (d, 1H, J = 16.3 Hz), 7.21-7.25 (m, 2H), 7.49-7.53 (m, 2H), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 396 (M +).

Table 24 33-1

¹ H NMR (δ CDCl ₃ ): 3.30 (t, 2H, J = 6.6 Hz), 3.74 (s, 3H), 4.42 (t, 2H, J = 6.6 Hz), 5.73 (s, 1H), 6.20-6.22 (m, 1H), 6.38 (d, 1H, J = 15.3 Hz), 6.56 (d, 1H, J = 15, 9 Hz), 6.72-6.74 (m, 1H), 6.78-6.79 (m, 1H), 6.90-6.93 (m, 1H), 7.06-7.08 (m, 1H), 7.11-7.13 (m, 1H), 7.16-7.20 (m, 1H), 7.25-7.31 (m, 2H), 7.56 (d , 1H, J = 15.8 Hz), 7.62 (d, 1H, J = 15.6 Hz), 7.63-7.67 (m, 1H), 8.56-8.59 (m, 1H), 16.07 (br s, 1H).
MS (EI) m / z 400 (M ⁺ ). 33-2

¹ H NMR (δ CDCl ₃ ): 3.31 (t, 2H, J = 6.6 Hz), 3.70 (s, 3H), 4.40 (t, 2H, J = 6.6 Hz), 6.14-6.17 (m, 1H), 6.49-6.52 (m, 1H), 6.57 (s, 1H), 6.64-6.67 (m, 1H), 6, 73-6.78 (m, 1H), 6.81-6.85 (m, 1H), 6.98 (d, 1H, J = 16.2 Hz), 7.01-7.08 (m, 4H), 7.17-7.21 (m, 1H), 7.22-7.28 (m, 1H), 7.30-7.34 (m, 1H), 7.64-7.69 ( m, 1H), 8.56-8.59 (m, 1H)
MS (EI) m / z 396 (M ⁺ ).

Table 25 34-1

¹ H NMR (δ CDCl ₃ ): 3.85 (s, 6H), 50028 (s, 2H), 6.20 (s, 2H), 7.25-7.28 (m, 1H), 7.51 (d, 1H, J = 7.8 Hz), 7.73-7.77 (m, 1H), 8.60-8.62 (m, 1H), 10.35 (s, 1H)
MS (EI) m / z 273 (M ⁺ ). 34-2

¹ H NMR (δ CDCl ₃ ): 3.72 (s, 3H), 3.85 (s, 6H), 5.25 (s, 2H), 5.71 (s, 1H), 6.17-6 19 (m, 1H), 6.23 (s, 2H), 6.36 (d, 1H, J = 15.4 Hz), 6.66-6.68 (m, 1H), 6.73- 6.75 (m, 1H), 6.97 (d, 1H, J = 16.0 Hz), 7.23-7.26 (m, 1H), 7.51 (d, 1H, J = 7, 7 Hz), 7.56 (d, 1H, J = 15.4 Hz), 7.71-7.75 (m, 1H), 8.03 (d, 1H, J = 16.0 Hz), 8 , 61 (d, 1H, J = 4.5 Hz), 16.26 (br s, 1H)
MS (EI) m / z 446 (M ⁺ ). 34-3

¹ H NMR (δ CDCl ₃ ): 3.69 (s, 3H), 3.84 (s, 6H), 5.24 (s, 2H), 6.13-6.15 (m, 1H), 6 26 (s, 2H), 6.47 (dd, 1H, J = 1.6 Hz, 3.7 Hz), 6.54 (s, 1H), 6.61-6.63 (m, 1H) 6.80 (d, 1H, J = 16.2 Hz), 6.97 (d, 1H, J = 16.2 Hz), 7.22-7.26 (m, 1H), 7.34 ( s, 2H), 7.53 (d, 1H, J = 7.9 Hz), 7.71-7.75 (m, 1H), 8.61 (d, 1H, J = 5.0 Hz)
MS (EI) m / z 442 (M ⁺ ).

Table 26 35-1

¹ H NMR (δ CDCl ₃ ): 3.76 (s, 3H), 3.87 (s, 3H), 5.25 (s, 2H), 5.81 (s, 1H), 6.58-6 61 (m, 2H), 6.64 (d, 1H, J = 16.0 Hz), 6.95-6.96 (m, 1H), 7.04 (d, 1H, J = 15.1 Hz), 7.16-7.17 (m, 1H), 7.22-7.26 (m, 1H), 7.44 (d, 1H, J = 15.1 Hz), 7.47-7 52 (m, 2H), 7.70-7.74 (m, 1H), 7.93 (d, 1H, J = 16.0 Hz), 8.60-8.62 (m, 1H), 15.93 (broad s, 1H)
MS (EI) m / z 417 (M ⁺ ). 35-2

¹ H NMR (δ CDCl ₃ ): 3.71 (s, 3H), 3.85 (s, 3H), 5.23 (s, 2H), 6.56-6.60 (m, 3H), 6 86-6.88 (m, 1H), 6.96 (d, 1H, J = 16.8 Hz), 6.97 (d, 1H, J = 16.1 Hz), 7.09-7, 11 (m, 1H), 7.22-7.25 (m, 1H), 7.29 (d, 1H, J = 16.8 Hz), 7.42 (d, 1H, J = 8.3 Hz ), 7.46 (d, 1H, J = 16.1 Hz), 7.51-7.53 (m, 1H), 7.70-7.74 (m, 1H), 8.59-8, 62 (m, 1H)
MS (EI) m / z 413 (M ⁺ ). 36-1

MS (EI) m / z 417 (M ⁺ ).

36-2

¹ H NMR (δ CDCl ₃ ): 3.70 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.60 (m, 3H), 6 89-6.90 (m, 2H), 6.93 (d, 1H, J = 16.5 Hz), 7.23-7.31 (m, 3H), 7.42 (d, 1H, J = 8.2 Hz), 7.43-7.44 (m, 1H), 7.51-7.54 (m, 1H), 7.71-7.75 (m, 1H), 8.61- 8.63 (m, 1H)
MS (EI) m / z 413 (M ⁺ ).

Table 27 37-1

MS (EI) m / z 414 (M ⁺ ). 37-2

¹ H NMR (δ CDCl ₃ ): 3.85 (s, 3H), 5.24 (s, 2H), 6.56-6.59 (m, 2H), 6.66 (s, 1H), 6 97 (d, 1H, J = 16.5 Hz), 7.13-7.18 (m, 2H), 7.22-7.25 (m, 1H), 7.30 (d, 1H, J = 16.5 Hz), 7.37-7.40 (m, 1H), 7.43 (d, 1H, J = 8.3 Hz), 7.51-7.53 (m, 1H), 7 56 (d, 1H, J = 16.1 Hz), 7.63-7.67 (m, 1H), 7.70-7.74 (m, 1H), 8.59-8.62 (m , 2H)
MS (EI) m / z 410 (M ⁺ ). 38-1

MS (EI) m / z 464 (M ⁺ ).

38-2

¹ H NMR (δ acetone-d ₆ ): 3.92 (s, 3H), 5.24 (s, 2H), 6.67 (dd, 1H, J = 2.6, 8.4 Hz), 6 76 (d, 1H, J = 2.6 Hz), 6.80 (s, 1H), 7.09 (d, 1H, J = 16.7 Hz), 7.30-7.33 (m, 1H), 7.37-7.49 (m, 4H), 7.54 (d, 1H, J = 9.0 Hz), 7.66-7.68 (d, 1H, J = 8.4 Hz ), 7.80-7.84 (m, 1H), 7.90-7.95 (m, 2H), 8.09-8.11 (m, 1H), 8.26-8.29 (m , 1H), 8.58-8.60 (m, 1H), 8.89 (dd, 1H, J = 1.9, 3.9 Hz)
MS (EI) m / z 460 (M ⁺ ).

Table 28 39-1

¹ H NMR (δ CDCl ₃ ): 3.87 (s, 3H), 5.25 (s, 2H), 5.78 (s, 1H), 6.46-6.48 (m, 1H), 6 51 (d, 1H, J = 15.4 Hz), 6.57-6.61 (m, 3H), 6.62 (d, 1H, J = 15.4 Hz), 7.22-7, 26 (m, 1H), 7.39 (d, 1H, J = 15.4 Hz), 7.45-7.49 (m, 2H), 7.50 (d, 1H, J = 7.7 Hz ), 7.70-7.74 (m, 1H), 7.90 (d, 1H, J = 15.4 Hz), 8.61 (d, 1H, J = 4.5 Hz)
MS (EI) m / z 403 (M ⁺ ). 39-2

¹ H NMR (δ CDCl ₃ ): 3.85 (s, 3H), 5.24 (s, 2H), 6.37-6.39 (m, 1H), 6.41-6.42 (m, 1H), 6.55-6.59 (m, 3H), 6.93-6.98 (m, 3H), 7.23-7.26 (m, 1H), 7.32 (d, 1H, J = 16.6 Hz), 7.39 (d, 1H, J = 1.6 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.53 (d, 1H, J = 7.9 Hz), 7.71-7.75 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 399 (M ⁺ ).

40-1

¹ H NMR (δ CDCl ₃ ): 2.36 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 5.75 (s, 1H), 6.07-6 09 (m, 1H), 6.43 (d, 1H, J = 15.4 Hz), 6.49-6.50 (m, 1H), 6.57-6.62 (m, 3H), 7.22-7.26 (m, 1H), 7.33 (d, 1H, J = 15.4 Hz), 7.45-7.48 (m, 1H), 7.50 (d, 1H, J = 7.7 Hz), 7.70-7.74 (m, 1H), 7.88 (d, 1H, J = 16.0 Hz), 8.60-8.62 (m, 1H), 16.02 (br s, 1H)
MS (EI) m / z 417 (M ⁺ ). 40-2

¹ H NMR (δ CDCl ₃ ): 2.33 (s, 3H), 3.85 (s, 3H), 5.23 (s, 2H), 5.99-6.01 (m, 1H), 6 24 (d, 1H, J = 3.15 Hz), 6.53 (s, 1H), 6.56-6.59 (m, 2H), 6.79 (d, 1H, J = 16.2 Hz), 6.87 (d, 1H, J = 16.2 Hz), 6.95 (d, 1H, J = 16.6 Hz), 7.21-7.25 (m, 1H), 7, 28 (d, 1H, J = 16.6 Hz), 7.43 (d, 1H, J = 8.3 Hz), 7.52 (d, 1H, J = 7.9 Hz), 7.70- 7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 413 (M ⁺ ).

Table 29 41-1

¹ H NMR (δ CDCl ₃ ): 1.95 (s, 3H), 2.27 (s, 3H), 3.86 (s, 3H), 5.25 (s, 2H), 5.74 (s , 1H), 6.38-6.42 (m, 2H), 6.57-6.62 (m, 3H), 7.23-7.31 (m, 2H), 7.47 (d, 1H , J = 9.3 Hz), 7.49-7.53 (m, 1H), 7.71-7.75 (m, 1H), 7.88 (d, 1H, J = 16.3 Hz) 8.59-8.63 (m, 1H)
MS (EI) m / z 431 (M ⁺ ).

41-2

¹ H NMR (δ CDCl ₃ ): 1.94 (s, 3H), 2.24 (s, 3H), 3.85 (s, 3H), 5.23 (s, 2H), 6.16 (s , 1H), 6.53-6.59 (m, 3H), 6.78 (d, 1H, J = 16.4 Hz), 6.83 (d, 1H, J = 16.4 Hz), 6 96 (d, 1H, J = 16.8 Hz), 7.22-7.26 (m, 1H), 7.30 (d, 1H, J = 16.8 Hz), 7.43 (d, 1H, J = 8.5 Hz), 7.51-7.53 (m, 1H), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 427 (M ⁺ ). 42-1

MS (EI) m / z 417 (M ⁺ ). 42-2

¹ H NMR (δ CDCl ₃ ): 3.85 (s, 3H), 3.95 (s, 3H), 5.24 (s, 2H), 6.47 (d, 1H, J = 2.0 Hz ), 6.57 (dd, 1H, J = 2.4, 8.6 Hz), 6.59 (d, 1H, J = 2.4 Hz), 6.60 (s, 1H), 6.93 (d, 1H, J = 16.7 Hz), 6.97 (d, 1H, J = 16.3 Hz), 7.03 (d, 1H, J = 16.3 Hz), 7.23-7 , 27 (m, 1H), 7.31 (d, 1H, J = 16.7 Hz), 7.41 (d, 1H, J = 8.3 Hz), 7.44 (d, 1H, J = 2.0 Hz), 7.51-7.54 (m, 1H), 7.71-7.75 (m, 1H), 8.61-8.63 (m, 1H)
MS (EI) m / z 413 (M ⁺ ).

Table 30 43-1

¹ H NMR (δ CDCl ₃ ): 2.00-2.06 (m, 2H), 2.39 (s, 3H), 2.55-2.59 (m, 2H), 2.71-2, 74 (m, 2H), 3.53-3.56 (m, 2H), 3.61-3.64 (m, 2H), 3.83 (s, 3H), 5.79 (s, 1H) 6.43 (d, 1H, J = 15.5 Hz), 6.48-6.50 (m, 1H), 6.65 (d, 1H, J = 15.8 Hz), 6.67- 6.70 (m, 2H), 7.12 (d, 1H, J = 3.1 Hz), 7.37-7.40 (m, 1H), 7.43-7.49 (m, 3H) 7.59-7.64 (m, 2H); 7.80 (d, 1H; J = 15.7 Hz)
MS (EI) m / z 441 (M ⁺ ). 43-2

¹ H NMR (δ CDCl ₃ ): 2.01-2.07 (m, 2H), 2.39 (s, 3H), 2.56-2.61 (m, 2H), 2.71-2, 75 (m, 2H), 3.51-3.54 (m, 2H), 3.60-3.63 (m, 2H), 3.81 (s, 3H), 6.46-6.48 ( m, 1H), 6.59 (s, 1H), 6.66-6.69 (m, 2H), 6.82 (d, 1H, J = 16.5 Hz), 7.00 (d, 1H , J = 16.4 Hz), 7.05-7.10 (m, 2H), 7.23 (d, 1H, J = 16.4 Hz), 7.31-7.34 (m, 1H) , 7.36-7.39 (m, 2H), 7.41-7.43 (m, 1H), 7.59 (d, 1H, J = 8.1 Hz)
MS (EI) m / z 437 (M ⁺ ). 44-1

MS (EI) m / z 480 (M ⁺ ).

44-2

¹ H NMR (δ CDCl ₃ ): 3.28 (t, 2H, J = 6.7 Hz), 3.79 (s, 3H), 3.84 (s, 3H), 4.40 (t, 2H , J = 6.7 Hz), 6.45-6.47 (m, 2H), 6.51 (dd, 1H, J = 2.3 Hz, 8.3 Hz), 6.62 (s, 1H ), 6.96 (d, 1H, J = 16.5 Hz), 7.05 (d, 1H, J = 3.0 Hz), 7.08 (d, 1H, J = 16.5 Hz), 7.14-7.18 (m, 1H), 7.23 (d, 1H, J = 16.5 Hz), 7.26-7.29 (m, 1H), 7.29-7.33 ( m, 2H), 7.40 (br.s, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7, 61-7.65 (m, 1H), 8.56-8.58 (m, 1H)
MS (EI) m / z 476 (M ⁺ ).

Table 31 45-1

¹ H NMR (δ CDCl ₃ ): 3.82 (s, 3H), 3.86 (s, 6H), 5.25 (s, 2H), 5.82 (s, 1H), 6.24 (s , 2H), 6.48 (d, 1H, J = 3.2 Hz), 6.66 (d, 1H, J = 15.4 Hz), 7.01 (d, 1H, J = 16.0 Hz ), 7.11 (d, 1H, J = 3.2 Hz), 7.23-7.26 (m, 1H), 7.37 (d, 1H, J = 1.3 Hz, 8.4 Hz ), 7.47 (s, 1H), 7.52 (d, 1H, J = 7.7 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.71-7.75 (m, 1H), 7.79 (d, 1H, J = 15.4 Hz), 8.07 (d, 1H, J = 16.0 Hz), 8.60-8.62 (m, 1H) , 16.23 (br s, 1H)
MS (EI) m / z 496 (M ⁺ ). 45-2

¹ H NMR (δ CDCl ₃ ): 3.79 (s, 3H), 3.85 (s, 6H), 5.24 (s, 2H), 6.26 (s, 2H), 6.45 (d , 1H, J = 3.2 Hz), 6.63 (s, 1H), 7.04 (d, 1H, J = 2.75 Hz), 7.11 (d, 1H, J = 16.1 Hz ), 7.22-7.27 (m, 2H), 7.31 (dd, 1H, J = 1.4 Hz, 8.3 Hz), 7.37 (s, 2H), 7.41 (s , 1H), 7.53 (d, 1H, J = 7.75 Hz), 7.57 (d, 1H, J = 8.3 Hz), 7.71-7.75 (m, 1H), 8 60-8.62 (m, 1H)
MS (EI) m / z 492 (M ⁺ ).

46-1

MS (EI) m / z 454 (M ⁺ ). 46-2

MS (EI) m / z 450 (M ⁺ ).

Table 32 47-1

¹ H NMR (δ CDCl ₃ ): 2.44-2.48 (m, 4H), 3.52 (s, 2H), 3.70-3.74 (m, 4H), 5.84 (s, 1H), 6.57-6.59 (m, 1H), 6.62 (d, 1H, J = 15.9 Hz), 6.66 (d, 1H, J = 15.8 Hz), 7, 29-7.31 (m, 1H), 7.35-7.38 (m, 2H), 7.39-7.42 (m, 1H), 7.50-7.53 (m, 2H), 7.57-7.58 (m, 1H), 7.63-7.67 (m, 2H), 7.81 (d, 1H, J = 15.7 Hz), 8.31 (br.s, 1H), 16.03 (br s, 1H)
MS (EI) m / z 414 (M ⁺ ). 47-2

¹ H NMR (δ CDCl ₃ ): 2.44-2.48 (m, 4H), 3.51 (s, 2H), 3.70-3.74 (m, 4H), 6.54-6, 55 (m, 1H), 6.63 (s, 1H), 7.03 (d, 1H, J = 16.3 Hz), 7.04 (d, 1H, J = 16.5 Hz), 7, 09 (d, 1H, J = 16.5 Hz), 7.20 (d, 1H, J = 16.2 Hz), 7.21-7.23 (m, 1H), 7.30-7.34 (m, 3H), 7.44-7.47 (m, 3H), 7.61 (d, 1H, J = 8.3 Hz), 8.16 (br s, 1H)
MS (EI) m / z 410 (M ⁺ ).

48-1

¹ H NMR (δ CDCl ₃ ): 2.49-2.56 (m, 4H), 2.59-2.64 (m, 2H), 2.81-2.86 (m, 2H), 3, 72-3.76 (m, 4H), 5.83 (s, 1H), 6.56-6.58 (m, 1H), 6.59 (d, 1H, J = 16.0 Hz), 6 65 (d, 1H, J = 16.0 Hz), 7.24 (d, 2H, J = 8.2 Hz), 7.28-7.30 (m, 1H), 7.39-7, 41 (m, 1H), 7.48 (d, 2H, J = 8.2 Hz), 7.57 (s, 1H), 7.61-7.65 (m, 2H), 7.80 (d , 1H, J = 16.0 Hz), 8.30 (br.s, 1H), 16.00 (br.s, 1H)
MS (EI) m / z 428 (M ⁺ ). 48-2

¹ H NMR (δ DMSO-d ₆ ): 2.41-2.44 (m, 4H), 2.49-2.55 (m, 2H), 2.74 (t, 2H, J = 7.7 Hz), 3.56-3.60 (m, 4H), 6.42 (br s, 1H), 6.73 (s, 1H), 6.96-7.39 (m, 8H), 7 , 43-7.56 (m, 4H), 11.04-11.17 (m, 1H), 12.88 (s, 1H)
MS (EI) m / z 424 (M ⁺ ).

Table 33 49-1

¹ H NMR (δ CDCl ₃ ): 1.81-1.88 On, 2H), 2.35-2.51 (m, 6H), 2.68 (t, 2H, J = 7.7 Hz), 3.70-3.77 (m, 4H), 5.83 (s, 1H), 6.57-6.62 (m, 2H), 6.66 (d, 1H, J = 15.9 Hz) 7.20-7.23 (m, 2H), 7.30-7.31 (m, 1H), 7.41 (dd, 1H, J = 1.4, 8.2 Hz), 7.47 -7.50 (m, 2H), 7.57-7.58 (m, 1H), 7.62-7.66 (m, 2H), 7.81 (d, 1H, J = 15.9 Hz ), 8.32 (br s, 1H) MS (EI) m / z 442 (M ⁺ ).

49-2

¹ H NMR (δ CDCl ₃ ): 1.81-1.88 (m, 2H), 2.39 (t, 2H, J = 7.6 Hz), 2.44-2.49 (m, 4H) 2.65 (t, 2H, J = 7.7 Hz), 3.72-3.76 (m, 4H), 6.54-6.56 (m, 1H), 6.64 (s, 1H ), 7.00-7.06 (m, 2H), 7.08 (d, 1H, J = 16.6 Hz), 7.16-7.23 (m, 4H), 7.33 (dd, 1H, J = 1.2, 8.5 Hz), 7.40-7.43 (m, 2H), 7.47-7.48 (m, 1H), 7.61 (d, 1H, J = 8.3 Hz), 8.19 (br s, 1H)
MS (EI) m / z 438 (M ⁺ ). 50-1

¹ H NMR (δ CDCl ₃ ): 2.29 (s, 3H), 2.35-2.61 (m, 8H), 3.53 (s, 2H), 5.84 (s, 1H), 6 , 57-6.59 (m, 1H), 6.61 (d, 1H, J = 15.9 Hz), 6.66 (d, 1H, J = 15.8 Hz), 7.29-7, 31 (m, 1H), 7.34-7.37 (m, 2H), 7.40-7.42 (m, 1H), 7.49-7.52 (m, 2H), 7.56- 7.58 (m, 1H), 7.64 (d, 1H, J = 8.3 Hz), 7.65 (d, 1H, J = 15.9 Hz), 7.81 (d, 1H, J = 15.7 Hz), 8.33 (br.s, 1H), 16.03 (br.s, 1H)
MS (EI) m / z 427 (M ⁺ ). 50-2

¹ H NMR (δ CDCl ₃ ): 2.29 (s, 3H), 2.40-2.57 (m, 8H), 3.51 (s, 2H), 6.54-6.56 (m, 1H), 6.63 (s, 1H), 7.02 (d, 1H, J = 16.4 Hz), 7.03 (d, 1H, J = 16.5 Hz), 7.08 (d, 1H, J = 16.5 Hz), 7.19 (d, 1H, J = 16.5 Hz), 7.20-7.23 (m, 1H), 7.29-7.34 (in, 3H ), 7.42-7.48 (m, 3H), 7.61 (d, 1H, J = 8.3 Hz), 8.23 (br s, 1H)
MS (EI) m / z 423 (M ⁺ ).

Table 34 51-1

¹ H NMR (δ CDCl ₃ ): 2.30 (s, 3H), 2.40-2.65 (m, 10H), 2.80-2.85 (m, 2H), 5.83 (s, 1H), 6.56-6.61 (m, 2H), 6.65 (d, 1H, J = 15.9 Hz), 7.23 (d, 2H, J = 8.1 Hz), 7, 28-7.30 (m, 1H), 7.40 (dd, 1H, J = 1.5 Hz, 8.05 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7, 56 (s, 1H), 7.61-7.65 (m, 2H), 7.80 (d, 1H, J = 15.9 Hz), 8.34 (br s, 1H), 15.96 (br.s, 1H)
MS (EI) m / z 441 (M ⁺ ). 51-2

¹ H NMR (δ CDCl ₃ ): 2.32 (s, 3H), 2.41-2.69 (m, 10H), 2.78-2.85 (m, 2H), 6.54-6, 56 (m, 1H), 6.63 (s, 1H), 7.01 (d, 1H, J = 16.5 Hz), 7.03 (d, 1H, J = 16.4 Hz), 7, 07 (d, 1H, J = 16.5 Hz), 7.16-7.22 (m, 3H), 7.22-7.24 (m, 1H), 7.33 (dd, 1H, J = 1.3 Hz, 8.2 Hz), 7.42 (d, 2H, J = 8.1 Hz), 7.48 (br.s, 1H), 7.62 (d, 1H, J = 8, 2 Hz), 8.19 (br.s, 1H)
MS (EI) m / z 437 (M ⁺ ). 52-1

¹ H NMR (δ CDCl ₃ ): 2.63 (t, 4H, J = 4.8 Hz), 2.89 (t, 2H, J = 5.8 Hz), 3.76 (t, 4H, J = 4.8 Hz), 4.20 (t, 2H, J = 5.8 Hz), 5.83 (s, 1H), 6.56-6.58 (m, 1H), 6.65 (d , 1H, J = 16.0 Hz), 6.76 (d, 1H, J = 16.0 Hz), 6.93 (d, 1H, J = 8.0 Hz), 6.96-7.00 (m, 1H), 7.28-7.34 (m, 2H), 7.40 (dd, 1H, J = 1.5 Hz, 8.0 Hz), 7.54-7.58 (m, 2H), 7.64 (d, 1H, J = 8.25 Hz), 7.80 (d, 1H, J = 16.0 Hz), 7.97 (d, 1H, J = 16.0 Hz) , 8.31 (br s, 1H), 16.01 (br s, 1H)
MS (EI) m / z 444 (M ⁺ ).

52-2

¹ H NMR (δ CDCl ₃ ): 2.62 (t, 4H, J = 4.6 Hz), 2.88 (t, 2H, J = 5.8 Hz), 3.75 (t, 4H, J = 4.6 Hz), 4.18 (t, 2H, J = 5.8 Hz), 6.52-6.54 (m, 1H), 6.61 (s, 1H), 6.90 (d , 1H, J = 7.7 Hz), 6.94-6.98 (m, 1H), 7.06 (d, 1H, J = 16.3 Hz), 7.13 (d, 1H, J = 16.7 Hz), 7.18-7.25 (m, 3H), 7.31-7.34 (m, 1H), 7.42-7.47 (m, 2H), 7.55 (dd , 1H, J = 1.6 Hz, 7.7 Hz), 7.60 (d, 1H, J = 8.2 Hz), 8.15 (br s, 1H)
MS (EI) m / z 440 (M ⁺ ).

Table 35 53-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.62 (m, 4H), 2.81-2.84 (m, 2H), 3.72-3.76 (m, 4H), 4, 13-4.17 (m, 2H), 5.84 (s, 1H), 6.56-6.59 (m, 1H), 6.60 (d, 1H, J = 15.9 Hz), 6 65 (d, 1H, J = 15.9 Hz), 6.92 (dd, 1H, J = 2.45 Hz, 8.1 Hz), 7.08-7.10 (m, 1H), 7 15 (d, 1H, J = 7.85 Hz), 7.27-7.32 (m, 2H), 7.39-7.42 (m, 1H), 7.57 (s, 1H), 7.60 (d, 1H, J = 15.9 Hz), 7.64 (d, 1H, J = 8.1 Hz), 7.81 (d, 1H, J = 15.9 Hz), 8, 32 (br.s, 1H), 15.97 (br.s, 1H)
MS (EI) m / z 444 (M ⁺ ). 53-2

¹ H NMR (δ CDCl ₃ ): 2.68 (br s, 4H), 2.90 (br s, 2H), 3.79 (br s, 4H), 4.21 (br s, 2H), 6.54-6.56 (m, 1H), 6.63 (s, 1H), 6.82-6.85 (m, 1H), 7.02 (d, 1H, J = 16, 3 Hz), 7.04-7.06 (m, 3H), 7.10 (d, 1H, J = 7.7 Hz), 7.19 (d, 1H, J = 16.3 Hz), 7 , 22-7.24 (m, 1H), 7.25-7.29 (m, 1H), 7.33 (dd, 1H, J = 1.4 Hz, 8.3 Hz), 7.48 ( s, 1H), 7.62 (d, 1H, J = 8.3 Hz), 8.19 (br s, 1H)
MS (EI) m / z 440 (M ⁺ ).

54-1

MS (EI) m / z 466 (M ⁺ ). 54-2

¹ H NMR (δ CDCl ₃ ): 3.29 (t, 2H, J = 6.7 Hz), 3.86 (s, 3H), 4.41 (t, 2H, J = 6.7 Hz), 6.47 (d, 1H, J = 2.3 Hz), 6.52-6.56 (m, 2H), 6.62 (s, 1H), 6.96 (d, 1H, J = 16, 5 Hz), 7.05 (d, 1H, J = 16.5 Hz), 7.15-7.23 (m, 3H), 7.24-7.28 (m, 1H), 7.30 ( d, 1H, J = 16.5 Hz), 7.33 (dd, 1H, J = 1.4 Hz, 8.3 Hz), 7.43 (d, 1H, J = 8.3 Hz), 7 49 (s, 1H), 7.61 (d, 1H, J = 8.7 Hz), 7.61-7.66 (m, 1H), 8.17 (br s, 1H), 8, 56-8.59 (m, 1H)
MS (EI) m / z 462 (M ⁺ ).

Table 36 55-1

¹ H NMR (δ CDCl ₃ ): 2.15 (s, 3H), 4.25-4.30 (m, 4H), 5.61 (s, 1H), 6.31 (d, 1H, J = 15.7 Hz), 6.86 (d, 1H, J = 8.3 Hz), 7.02 (dd, 1H, J = 2.0 Hz, 8.3 Hz), 7.05 (d, 1H , J = 2.0 Hz), 7.48 (d, 1H, J = 15.7 Hz), 15.41 (br s, 1H) 55-2

MS (EI) m / z 493 (M ⁺ ).

55-3

¹ H NMR (δ CDCl ₃ ): 2.58-2.61 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz), 3.73-3.76 (m, 4H) 3.86 (s, 3H), 4.14 (t, 2H, J = 5.7 Hz), 4.26-4.27 (m, 4H), 6.48-6.51 (m, 2H ), 6.58 (s, 1H), 6.84 (d, 1H, J = 8.3 Hz), 6.89 (d, 1H, J = 16.5 Hz), 6.93-6.99 (m, 3H), 7.01 (d, 1H, J = 1.8 Hz), 7.29 (d, 1H, J = 16.5 Hz), 7.43 (d, 1H, J = 8, 7 Hz)
MS (EI) m / z 489 (M ⁺ ). 56-1

¹ H NMR (δ CDCl ₃ ): 2.56-2.60 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz), 3.72-3.75 (m, 8H) 3.88 (s, 6H), 4.15 (t, 4H, J = 5.7 Hz), 5.79 (s, 1H), 6.48 (d, 2H, J = 2.5 Hz) 6.51 (dd, 2H, J = 2.5 Hz, 8.5 Hz), 6.62 (d, 2H, J = 16.0 Hz), 7.47 (d, 2H, J = 8, 5 Hz), 7.77 (d, 2H, J = 16.0 Hz), 16.13 (br.s, 1H)
MS (EI) m / z 594 (M ⁺ ). 56-2

¹ H NMR (δ CDCl ₃ ): 2.57-2.61 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz), 3.73-3.76 (m, 8H) 3.86 (s, 6H), 4.14 (t, 4H, J = 5.7 Hz), 6.47-6.52 (m, 4H), 6.61 (s, 1H), 6, 97 (d, 2H, J = 16.5 Hz), 7.30 (d, 2H, J = 16.5 Hz), 7.44 (d, 2H, J = 8.3 Hz)
MS (EI) m / z 590 (M ⁺ ).

Table 37 57-1

MS (EI) m / z 436 (M ⁺ ).

57-2

¹ H NMR (δ CDCl ₃ ): 3.81 (s, 3H), 5.23 (s, 2H), 6.62 (s, 1H), 6.80 (s, 1H), 6.89 (d , 1H, J = 16.4 Hz), 6.97 (d, 2H, J = 8.7 Hz), 7.04 (d, 1H, J = 16.4 Hz), 7.07-7.12 (m, 1H), 7.10 (d, 1H, J = 16.3 Hz), 7.17 (d, 1H, J = 16.3 Hz), 7.18-7.30 (m, 3H) , 7.41 (d, 2H, J = 8.7 Hz), 7.52 (d, 1H, J = 7.9 Hz), 7.58 (d, 1H, J = 7.8 Hz), 7 70-7.74 (m, 1H), 8.61 (d, 1H, J = 4.4 Hz)
MS (EI) m / z 432 (M ⁺ ). 58-1

MS (EI) m / z 466 (M ⁺ ). 58-2

¹ H NMR (δ acetone-d ₆ ): 3.84 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 6.44-6.46 (m, 1H) 6.65-6.68 (m, 2H), 6.74 (d, 1H, J = 2.3 Hz), 7.04-7.09 (m, 2H), 7.21 (d, 1H , J = 3.2 Hz), 7.29-7.34 (m, 2H), 7.36-7.41 (m, 2H), 7.46 (dd, 1H, J = 1.4, 8 , 7 Hz), 7.53 (d, 1H, J = 8.3 Hz), 7.56-7.58 (m, 1H), 7.70-7.72 (m, 1H), 7.80 -7.84 (m, 1H), 8.58-8.60 (m, 1H), 11.93 (br s, 1H)
MS (EI) m / z 462 (M ⁺ ).

Table 38 59-1

¹ H NMR (δ CDCl ₃ ): 2.45 (s, 3H), 3.83 (s, 3H), 5.23 (s, 2H), 5.82 (s, 1H), 6.45-6 50 (m, 2H), 6.67 (d, 1H, J = 15.8 Hz), 6.84-6.87 (m, 2H), 7.13 (d, 1H, J = 3.0 Hz), 7.22-7.27 (m, 1H), 7.37-7.40 (m, 1H), 7.48-7.52 (m, 2H), 7.56-7.63 ( m, 2H), 7.70-7.74 (m, 1H), 7.83 (d, 1H, J = 15.8 Hz), 7.89 (d, 1H, J = 15.8 Hz), 8.60-8.62 (m, 1H)
MS (EI) m / z 450 (M ⁺ ). 59-2

¹ H NMR (δ CDCl ₃ ): 2.41 (s, 3H), 3.80 (s, 3H), 5.22 (s, 2H), 6.46-6.48 (m, 1H), 6 63 (s, 1H), 6.82-6.87 (m, 3H), 7.06 (d, 1H, J = 3.1 Hz), 7.07 (d, 1H, J = 16.5 Hz), 7.21-7.28 (m, 3H), 7.31-7.33 (m, 1H), 7.40-7.42 (m, 1H), 7.50-7.54 ( m, 2H), 7.59 (d, 1H, J = 8.2 Hz), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)
MS (EI) m / z 446 (M ⁺ ).

Pharmacological Test Example 1: Determination of Tau Aggregation Inhibitory Activity

The recombinant three-repeat, microchannel binding domain (3R-MBD) of the tau protein is expressed in E. coli, purified and used in experiments. The purified tau solution is diluted with 50 mM Tris-HCl buffer (pH 7.6) to a final concentration of 10 μM. Test compounds are prepared using dimethyl sulfoxide (hereinafter referred to as DMSO) at their 20-fold final concentrations and added to the tau solution so that the DMSO concentration is 5%. Heparin was added to the resulting solution so that the final concentration was 10 μM, and the plate was allowed to stand at 37 ° C for 16 hours. Thioflavin T is added to the plate so that the concentration is 10 μM, and the fluorescence intensity is measured using a device that reads from a fluorescence plate (PerkinElmer, Inc.) (excitation wavelength: 440 nm; fluorescence at a wavelength: 486 nm).

The final concentration of each of the compounds at the time of measurement is 0.1, 0.3, 1, 3, and 10 μM. A sample to which only DMSO is added is used as a negative control, and its fluorescence intensity is taken as 0% inhibitory activity to determine a 50% inhibitory concentration (IC ₅₀ ) of each compound. The results are presented in table 39. Table 39 also presents the calculated maximum inhibition (%) for compounds exhibiting particularly high maximum inhibition (%) at the concentrations used to determine the inhibitory activity of tau aggregation.

Table 39 Compound IC ₅₀ (μm) Maximum Inhibition (%) Example 16-2 0.6 - Example 17-2 0.65 - Example 19-4 0.51 - Example 20-3 0.55 89 Example 21-2 - 89 Example 22-2 0.66 90 Example 23-2 0.59 92 Example 25-2 0.84 - Example 27-3 - 91 Example 28-2 - 93 Example 32-5 0.64 90 Example 42-2 0.83 - Example 43-2 - 92 Example 53-2 0.84 -

As follows from table 39, some of the compounds of the present invention demonstrate a particularly high inhibitory activity against aggregation of tau. Compounds that exhibit the highest inhibition ability are expected to have an enhanced therapeutic effect and are therefore most preferred.

Pharmacological Test Example 2: Determination of β-Secretase Inhibitory Activity

Β-secretase inhibition activity was measured using a BACE-1 FRET assay kit (Invitrogen). Test compounds are prepared using DMSO at their 30-fold final concentrations and added to the assay buffer so that the DMSO concentration is 10%. Equal volumes of human recombinant β-secretase (1 U / ml) and a fluorescent peptide substrate (750 nM), each dissolved in assay buffer, were added to each solution, and the resulting solutions were allowed to stand for 1 hour. Fluorescence intensity is measured using a device reading data from a fluorescence plate (excitation wavelength: 545 nm; fluorescence wavelength: 590 nm).

The final concentration of each of the compounds at the time of measurement is 0.1, 0.3, 1, 3, and 10 μM, and 0.3, 1, 3, 10, and 30 μM, or 1, 3, 10, 30, and 100 μM. A sample to which only DMSO is added is used as a negative control, and its fluorescence intensity is taken as 0% inhibitory activity to determine the 50% inhibitory concentration (IC ₅₀ ) of each of the compounds for β-secretase. The amino acid sequence of the fluorescent peptide substrate corresponds to Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Lys-Arg, in which the Ser residue at position 1 is labeled with a fluorescent donor (Cy3), and Lys at position 9 is labeled with a fluorescence quencher (Cy5Q )

The compounds of the present invention show high inhibitory activity against β-secretase.

Pharmacological Test Example 3: Determination of Aβ Aggregation Inhibitory Activity

Aβ 1-42 (Peptide Institute, Inc.) is dissolved in 0.1% ammonia water so that the concentration is 0.5 mM, and then diluted with PBS to 20 μM. Test compounds are prepared in DMSO at their 100-fold final concentrations and then diluted with PBS so that the DMSO concentration is 2%. Aβ solution and solutions of each of the test compounds were mixed in an equivalent ratio, and the resulting mixture was allowed to stand at 37 ° C for 24 hours. Equal volumes of thioflavin T solution were added to each of the mixtures, the concentrations of which were adjusted to 6 μM using 100 mM Tris-glycine buffer (pH 8.5). Fluorescence intensity is measured using a device that reads data from a fluorescent tablet (excitation wavelength: 440 nm; fluorescence wavelength: 486 nm).

The final concentrations of each of the compounds at the time of measurement are 0.1, 0.3, 1, 3, and 10 μM, or 2, 4, 8, and 16 μM. A sample to which only DMSO is added is used as a negative control, and its fluorescence intensity is taken as 0% inhibitory activity. Using the fluorescence intensity of the control sample, taken as 0%, calculate the 50% inhibitory concentration (IC ₅₀ ) of each of the compounds to evaluate the inhibitory activity of Aβ aggregation of each of the compounds.

The compounds of the present invention show high inhibitory activity against Aβ aggregation.

Pharmacological Test Example 4: Measurement of brain concentration after oral administration

Each of the compounds of the present invention shown in Tables 40 and 41 and the compound of Example 2 in JP 2012-229208 A was orally administered to ICR mice (males, 7 weeks old) in a single dose of 5 mg / kg. 3, 6, and 9 hours after administration, 1, 3, 6, and 9 hours after administration, or 1, 3, 6, 9, and 24 hours after administration, mice are injected with saline in the heart during inhalation anesthesia with isofuran and the whole brain is removed. Saline is added to the collected brain in an amount corresponding to the double wet mass of the brain, and the brain is homogenized. Then equal volumes of methanol are added and the resulting mixture is deproteinized. The concentration of each of the compounds in the sample is measured using LC / MS / MS. The test results are presented in tables 40 and 41.

Table 40 Compound AUC _{0-9 hours} in the brain (ng⋅h / g-tissue) Example 22-2 458 Example 44-2 869 JP 2012-229208 A, Example 2 224

Table 41 Compound AUC _{0-24 hours} in the brain (ng⋅h / g-tissue) Example 14-2 24639 Example 18-2 9781 Example 19-4 3499 Example 20-3 5306 Example 27-3 1302 JP 2012-229208 A, Example 2 from 645 to 677

Industrial applicability

The compound of the present invention can be used as a prophylactic drug, therapeutic drug, and the like. for the treatment of Alzheimer's disease, and therefore the present invention can be applied in industrial fields, such as the pharmaceutical industry.

Claims (29)

1. The compound represented by the formula:

2. The compound represented by the formula:

or a pharmaceutically acceptable salt thereof. 3. The compound represented by the formula:

or

or a pharmaceutically acceptable salt thereof. 4. The compound represented by the formula:

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or a pharmaceutically acceptable salt thereof.